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2003

Veterinary

Developmental Anatomy

Veterinary EmbryologyClass Notes

(CVM 6100)

by

Thomas F. Fletcher, DVM, PhD

and

Alvin F. Weber, DVM, PhD

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CONTENTS

Early Embryogenesis .....................................................3

Musculo-Skeletal Development ...................................15

Serous Body Cavities....................................................21

Cardiovascular System ................................................23

Digestive System ...........................................................30

Respiratory System ......................................................36

Urinary System.............................................................39

Genital System ..............................................................42

Face, Nasal Cavity, Mouth, & Pharynx......................47

Nervous System & Special Senses...............................54

Appendix I. Gametogenesis .........................................66

Appendix II. Mitosis and Meiosis ...............................68

Appendix III. List of Anomalies..................................72

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Early Embryogenesis

Embryonic developmentEmbryogenesis, the formation of body structures & organs (organogenesis),requires cell division (proliferation) and cell differentiation (specialization)to produce a variety of cell types and extracellular products. Regulation ofgene expression (protein production) is the ultimate explanation for theprocess of cell differentiation and embryogenesis. Genetic expression willdepend on previous genetic history (commitment) and current cellularenvironment (intercellular communication).

Cell differentiation is the result of cells expressing some genes and suppressing others withina common genome. Cells differ because they’re producing different proteins & peptides.

Proteins & peptides are:— structural components (cytoskeleton or extracellular structures)— enzymes (controlling cell metabolism)— secretory products (e.g., hormones; digestive enzymes; etc.)— channels & pumps (passage of molecules across membranes)— receptors (communication, etc.)

Fertilization = the union of a haploid oocyte and a haploid spermatozoon to produce a diploidzygote (a single cell capable of developing into a new individual)

Oocyte (enveloped by a zona pellucida (glycoprotein membrane) and corona radiata (granulosa cells) at ovulation)

— selective follicles mature at each cycle (in response to circulating FSH hormone from the pituitary)— primary oocytes resume meiosis as follicles mature (having been suspended in Meiosis I since

before birth by inhibitory secretion of follicle granulosa cells)— secondary oocytes complete meiosis if fertilization takes place, otherwise the oocytes degenerate.

Spermatozoa (several hundred million per ejaculate)

— propelled from vagina to uterine tube by contraction of female genital tract— undergo capacitation (removal of surface proteins that impede making contact with oocyte)— undergo acrosomal reaction after binding to zona pellucida (binding triggers release of

acrosomal enzymes that denature zona pellucida proteins to facilitate penetrationby the reactive sperm and preclude binding by other sperm).

specialized cell

> stellate neuron, etc.

stem cell committed cells

> neural epithelium

> neuroblast

> glioblast

> pyramidal neuron

> astrocyte

> oligodendrocyte

ectoderme.g.,

Cell Differentiation

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Fertilization details:Fertilization begins with gamete fusion (zygote formation). This takes place in the uterine tube,

near the ovary . . .— to begin, a spermatozoon binds to a specific glycoprotein in the zona pellucida

surrounding the oocyte [the recognition process precludes union with foreign sperm];— the spermatozoon releases degradative enzymes (acrosomal reaction) that allow it to

penetrate the zona pellucida;— spermatozoon and oocyte plasma membranes fuse (secondary oocyte completes meiosis);— the oocyte precludes fusion with other sperm by immediately canceling its

membrane potential (via Ca++ influx) and then by denaturing its zona pellucidavia enzymes released by exocytosis from cytoplasmic granules;

— male & female haploid pronuclei make contact, lose their nuclear membranes, and beginmitosis (mitosis begins 12 hours after sperm fusion. DNA synthesis takes place before mitosis)

Fertilization ends with the initiation of zygote cell division (the start of cleavage)

Cleavage. . .refers to the series of mitotic divisions by which a relatively large zygote is fractionated into

numerous “normal size” cells. Each daughter cell of the cleavage process is termed a blastomere.— cleavage begins with a zygote, progresses through a morula stage and terminates at the

blastocyst (blastula) stage— the first eight blastomeres are undifferentiated and have identical potential in domestic mam-

mals; thereafter, blastomeres differentiate into inner & outer cells with different missions

Note: The first cleavage division occurs 1 to 5 days following ovulation (depending on species),thereafter cells divide about once every 12 hours;

As many as eight generations of mitoses may occur without intervening cell growth (cytoplasmic increase). Thus, e.g., a 150 mm diameter zygote can becomes a collection of 256cells, each 7 mm diameter.

A morula [L.= small mulberry] is a solid ball of blastomeres, within a zona pellucida. Amorula typically consists of 16 to 64 blastomeres = four to six cell divisions. Blastomeres are compacted; cellspacked on the inside differentiate from those along the surface of the morula:

— outer blastomeres become flattened and form tight junctions (resulting in reduced permeabil-ity to fluids); they develop the capacity to secrete fluid (internally); they are destined tobecome trophoblasts which form the chorion & amnion (fetal membranes);

— inner blastomeres form gap junctions to maximize intercellular communication; they aredestined to become inner cell mass which forms the embryo plus two fetal membranes.

FirstCleavage Division

SecondCleavage Division Morula

Blastula(Blastocyst)

zonapellucida

blastomeres

outerblastomeres

innerblastomeres trophoblasts

blastocoele

innercell mass

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Note: • As few as three inner blastomeres are sufficient to produce an entire embryo (and adult).• When a morula leaves the uterine tube and enters the uterus (uterine horn) it is at about

the 16-cell stage, around 4 to 7 days after fertilization (depending on species).• The 32-cell stage morula (5-7 days post ovulation) is ideal for embryo transfer in cattle.

A blastocyst (or blastula) consists of a large number of blastomeres arranged to form ahollow (fluid filled) sphere/cylinder containing an inner cell mass (embryoblast) = a group of cellslocalized inside one pole (end) of the blastula. The surface cells of the blastocyst are designatedtrophoblasts, and the fluid cavity is called a blastocoele:

Cleavage in fish, reptiles, and birdsLarge quantities of yolk impede cell division during cleavage. A blastodisc (rather

than a spherical or elliptical blastocyst) is formed at the animal pole of the egg.A telolecithal ovum (egg with large amounts of asymmetrically distributed yolk) has its nucleus

displaced to one end (pole). Such an ovum has an animal pole where the nucleus is located and an oppositevegetal pole where yolk is concentrated. Cleavage is partial (meroblastic): cells divide more rapidly(completely) at the animal pole than at the vegetal pole. The result is many, small blastomeres (micromeres)at the animal pole and few, large macromeres at the vegetal pole. (Cleavage is completed and gastrulation isunderway and the conceptus is composed of about 60,000 cells by the time a chicken egg is laid.)

In contrast, mammalian ova have meager amounts of yolk (oligolecithal ova) which is uniformlydistributed (isolecithal). Cleavage is holoblastic (total): each blastomere division produces two equal-sizedaughter cells. Thus animal and vegetal poles are not evident in mammalian ova.

TWINSMonozygotic: identical (same genetic composition) twins can result from either: 1] separation of early blastomeres (up to the 8-cell stage)—each separate

blastomere(s) develops into an independent conceptus [conceptus = embryo andplacental membranes]; or

2] separation of inner blastomeres within a single morula—each separateblastomere(s) develops into an independent embryo and the two embryos share acommon placenta (this is less common than the first possibility).

Note: Diplopagus (Siamese) twins, as well as double heads, extra limbs, etc.anomalies are the result of separations later in embryonic development.

Dizygotic: fraternal twins result when two (or more) zygotes develop “independently”during the same pregnancy (independence can be compromised by fusion of fetalmembranes and blood supplies). It is possible for fraternal blastomeres to merge andproduce a single conceptus that has two different genotypes represented among itspopulation of cells (a chimera).

NOTE:Ectoderm, mesoderm and endoderm are designated primary germ layers because origins

of all organs can be traced back to these three layers.Ectoderm forms epidermis of the skin, epithelium of the oral and nasal cavities, and the

nervous system and sense organs.Mesoderm forms muscle and connective tissue, including bone, and components of the

circulatory, urinary and genital systems.Endoderm forms mucosal epithelium and glands of respiratory and digestive systems.

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trophoblastlayer

degeneratingtrophoblast

hypoblastlayer

inner cell mass

embryonic disc

epiblast

Hypoblast Formation (three stages)

delaminatinghypoblast cells

blastocoele

embryonic discmagnified

trophoblastlayer

hypoblastlayer

coelom

yolk sac(primitive gut)

coelom

yolk sac(primitive gut)

epiblast

GastrulationGastrulation is the morphogenic process that gives rise to three germ layers: ectoderm,

mesoderm, and endoderm. In a gastrula [Gr.= little stomach] one can see evidence of primitive gut formation.

Gastrulation includes the following sequence, beginning with a blastocyst:

— a thickened embryonic disc becomes evident at the blastula surface, due to proliferation ofinner cell mass cells; also, trophoblast cells overlaying the inner cell mass degenerate indomestic animals (in some mammals, e.g., mouse and human, trophoblast cells overlaying the inner cell

mass separate and, instead of degenerating, become amnionic wall)

— from the inner cell mass, cells proliferate, break loose (delaminate), and migrate to form a newcell layer inside of the trophoblast layer; the new layer of cells is called the hypoblast; theremaining inner cell mass may henceforth be called epiblast

— differential growth of the epiblast generates a pair of ridges separated by a depression calledthe primitive streak [NOTE: The primitive streak indicates the start of gastrulation. Itdefines the longitudinal axis of the embryo. The streak is the source of mesoderm.]

— the separation of the hypoblast layer from the epiblast establishes a fluid space (coelom) deepto the primitive streak; the coelom is destined to become trunk cavities of the future animal

— epiblast cellular proliferation along primitive streak ridges becomes the source of a cellularmigration through the streak depression

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Dorsal View of Embryonic Disc

NOTE: Arrows indicate the spread of primary mesenchyme through the primitive streak and between the epiblast and hypoblast

primitivestreak

primitivenode

primarymesenchyme

notochord

— initial migrating cells join thehypoblast layer, forming embry-onic endoderm (vs. the hypoblastwhich forms extra-embryonic endodermof fetal membranes)

— the majority of migrating cellsenter the coelom as primarymesenchyme which is destined tobecome mesoderm; the primarymesenchyme migrates laterallyand cranially (but not along themidline region directly cranial tothe primitive streak where noto-chord will form)

— cavitation re-establishes a coelomin the lateral mesoderm which is split into two layers bordering the coelom—the somaticmesoderm is attached to the ectoderm and the splanchnic mesoderm is joined to endoderm.

— the remaining epiblast becomes ectoderm which forms skin epidermis and nervous system

Formation of the notochord:The notochord is a rod-shaped aggregate of cells located cranial to the primitive streak of

the embryo. It occupies the midline space between ectoderm and endoderm that was not invaded bymigrating mesodermal sheets.

The notochord is important because it induces formation of the head, the nervous system, andsomites. It marks the future location of the vertebral column and base of the cranium. Its ultimatefate is to become the nucleus pulposus of intervertebral discs.

The notochord develops from the primitive node located at the cranial end of the primitive streak. From thenode, mesoderm-forming cells proliferate and migrate forward into the future head region where they become the rod-shaped notochord.

epiblast (ectoderm)

hypoblast endoderm primary mesenchyme (mesoderm

primitive streak

endoderm

ectoderm

mesoderm cells

notochord cellsprimitive node

primitive streak head process

Longitudinal Section Through Primitive Node and Notochord

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Somite formationSomites are blocks of mesoderm located

just lateral to the notochord. Generally, there are apair of somites for every vertebra and a half dozensomite pairs in the head. The number of somites inan embryo is indicative of age because somitesdevelop chronologically, in craniocaudal order.

Note: The ventromedial portion of a somite developsinto a sclerotome (which forms vertebrae, ribs, &basal bones of the skull), the lateral portionbecomes a dermatome (skin dermis), and the restof the somite forms a myotome (skeletal muscle).

Somites develop as follows:— mesoderm accumulates on each side of the

notochord; this medially positioned meso-derm is designated paraxial mesoderm

— progressing from rostral to caudal over time,transverse fissures divide the paraxialmesoderm into blocks — each block is asomite (cells within a block re-orient 90°, fromtransverse to the notochord to longitudinal to thenotochord)

— head (occipital) somites develop from proliferation of local mesenchyme lateral to the cranialend of the notochord

— rostral to the notochord, mesenchyme forms quasi-somites, called somitomeres; they migrateinto branchial arches and form muscles of the jaw, face, pharynx, and larynx.

NOTE:Mesoderm can exist in two morphologic forms: mesenchyme and epithelium:

Mesenchyme features aggregates of stellate cells within an abundant extracel-lular matrix composed of fluid and macromolecules (polymers).Epithelium refers to organized cells having distinct apical and basal surfaces,the latter commonly rests on a basal lamina produced by epithelial secretion.

Mesoderm can transform from a mesenchyme to an epithelium and vice versa: Themesoderm that streams through the primitive streak is primary mesenchyme.Somatic, splanchnic, and somite mesoderm can be temporarily an epithelium.The temporary epithelium transforms to a secondary mesenchyme whichultimately forms muscle and connective tissue (including cartilage, bone,ligaments, tendons, dermis, fascia, and adipose tissue).

Thus, the term “mesenchyme” refers to the morphologic appearance of embryonictissue. Although most mesenchyme is mesoderm, the other germ layers canalso form mesenchyme during organ development.

otic placode

optic placode

heart

umbilicalstalk

somites

branchialarches

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Neurulation

ectoderm

neuroectoderm

notochord

neural groove

neural tube

paraxial mesodermintermediate mesoderm

lateral mesoderm

coelom

somite

neural crest

somaticsplanchnic

endoderm

Early Formation of the Nervous System (Neurulation)

Neurulation refers to notochord-induced transformation of ectoderm to nervous tissue. Itbegins in the region of the future brainand progresses caudally into theregion of the future spinal cord.

The following steps are involved inneurulation:

— ectodermal cells overlaying thenotochord become tall colum-nar (neuroectoderm) and forma thickened area designatedthe neural plate (other ectoder-

mal epithelium becomes flattened)

— a neural groove is formed asedges of the neural platebecome raised on each side ofa midline depression

— a neural tube is formed as theneural groove is closed bymidline merger of its dorsaledges; the tube separates fromnon-neural ectoderm whichunites dorsal to it; tube formationbegins in the cranial cervical regionof the central nervous system andprogresses cranially and caudallyuntil anterior and posterior neuropores, the last openings, finally close

— bilaterally, where the neural groove is joined to non-neural ectoderm, cells detach as theneural groove closes; the cells proliferate and assume a position dorsolateral to the neuraltube—forming neural crest.

NOTE: Neural crest cells are remarkable for the range of structures they form. Somecells migrate dorsally and become pigment cells in skin. Others migrate ventrallyand become neurons and glial cells of the peripheral nervous system, or adrenalmedulla cells. In the head, neural crest forms mesenchyme (ectomesenchyme)which becomes meninges, bone, fascia, and teeth.

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Development of a Cylindrical BodyThe early embryo is flat, but the vertebrate body plan features a cylindrical theme—various

cylindrical structures (derivatives of the gut, neural tube, notochord, etc.) enclosed within a cylindri-cal body. Transition from a flat embryo to a cylindrical one involves the following developments:

Head Process:• The cranial end of the embryo grows dorsal

and forward so that it projects above an areaoriginally in front of the embryo.

• The head process elongates by growth fromits base in front of the primitive node. Consequently,the most anterior part of the embryo is the oldest. Theelongation incorporates the most anterior half-dozen somitesinto the future head.

• Within the head process, endoderm is re-flected ventrally upon itself, forming a blind-endedforegut (future pharynx).

Tail Fold:• At the caudal end of the embryo, a tail fold is

formed in a manner similar to that of the headprocess.

• Folded endoderm encloses a blind hindgut .

Lateral Body Folds:• As the head process elongates upward &

forward, a subcephalic pocket (space) is formedventral to the head process, between the headprocess and extra-embryonic tissue. The bilateralmargins of the pocket are lateral body folds—which constitute the continuity between the el-

evated embryo and therelatively flat extra-embryonic tissue.

• Similar folds existcaudally in associationwith the tail process.

• As the embryogrows and is elevateddorsally, lateral bodyfolds adduct and joinventrally, establishing a tubular embryo separated from flattened extra-embryonic tissue.

• Progressing caudally from the head process and cranially from thetail fold, ventral fusion of lateral body folds stops at the umbilicus—leaving a ventral opening in the body wall that allows vessels and theyolk sac and allantois to enter the embryo (and communicate with the gut).

DorsalView

primitivestreak

primitivenode

elevatedhead

process

lateralbodyfold

oral plate

head process

subcephalicpocket

pharynx

ectoderm

endodermmesoderm

yolk sac

Three Stages ofHead Process

Formation(longitudinal views)

head process

yolk sacpericardium

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Mesoderm = somite = intermediate = lateral

neural tubenotochord

foregut

mesentery

yolksac

embryoniccoelom

extra-embryoniccoelom

somatopleuresplanchnopleure

LateralBody Folds

• Ventral fusion of lateral body foldsdistinguishes the embryo from extra-embryonic tissue (fetal membranes):

Embryonic coelom (future body cavitiesof the trunk) is distinguished from extra-embryonic coelom.

Somatopleure (somatic mesoderm +ectoderm) that forms body wall is distin-guished from that forming fetal membranes(chorion and amnion).

Splanchnopleure (splanchnic mesoderm+ endoderm) merges bilaterally to form gutand mesentery, differentiated from extra-embryonic yolk sac (and allantois).

Pharyngeal (Branchial) Arches:In the head region, anterior to the embryonic coelom, mesenchyme between ectoderm and

endoderm forms a series of dorso-ventral arches demarcated by grooves. Only three pharyngealarches are externally evident in mammals. Each arch contains a vessel (aortic arch). Within each arch, mesoder-mal mesenchyme which gives rise to muscle is augmented by ectomesenchyme (migrated from neural crest) which givesrise to bone and fascia.

The first branchial arch develops into upper and lower jaws, the second into hyoid bones andmuscles of the face, and the remaining arches form hyoid bones, larynx and associated muscles.Each arch is innervated by a particular cranial nerve.

The pharynx (foregut) develops five bilateral diverticula that internally demarcate the pha-ryngeal arches. These pharyngeal pouches develop into auditory tube, parathyroid glands, thymus,etc.

NOTE: In fish, five or six branchial [Gr. = gill] arches are well developed. Cells degenerate wherebranchial grooves and pharyngeal pouches meet so that the pharynx communicates with theoutside (this occurs only temporarily between the first two arches in mammals). The first archforms the jaw apparatus and the rest form gill arches separated by gill slits.

Flexures:The tube-shaped embryo undergoes three flexures that make it C-shaped. The first occurs in

the future midbrain region, the second in the future neck region, and the third occurs in the tailregion.

Cardiovascular system:• The cardiovascular system develops early (just after the nervous system) as the embryo

enlarges to an extent that diffusion alone becomes inadequate for tissue preservation.• Angiogenesis (formation of blood vessels) begins in splanchnic mesoderm of the yolk sac,

in the form of blood islands composed of mesenchyme and hemocytoblasts. The latter forms bloodcells and the mesenchyme forms vesicles lined by endothelium. The vesicles coalesce to formvascular channels and then blood vessels (the latter extend by budding).

• Vessels are formed first in extra-embryonic tissue: vitelline (yolk sac) and umbilical (allan-toic) vessels appear first.

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• Ventral to the pharynx, bilateral vessels merge to form a tubular heart; dorsal and ventralaortae are connected by aortic arches; cranial and caudal cardinal veins return embryonic blood tothe heart and umbilical veins return placental blood to the heart (none of these vessels will persist assuch in the adult).

Placentation:

The placenta is the area(s) of apposition between uterine lining and fetal membranes wheremetabolites are exchanged for sustaining pregnancy.

Apposition areas (placental types) may be diffuse (pig), zonary (carnivore), discoid (primates& rodents), or involve placentomes. A placentome is a discrete area of interdigitation between amaternal caruncle and a fetal cotyledon. Equine placentas are microcotyledonary (microplacentomesare distributed diffusely). Ruminant placentas consist of rows of relatively large placentomes.

Placentas (placentae) may also be classified according to the tissue layers separating fetal and maternal blood.Uterine epithelium, connective tissue and endothelium may be eroded, giving rise to four placental types:epitheliochorial (swine, equine, cattle); syndesmochorial (sheep, goats); endothelial chorial (carnivore); and hemochorial(primates & rodents).

Fetal membranes:Four fetal membranes develop in a conceptus. Two arise from the trophoblast layer of the

blastocyst and are continuous with the somatopleure of the embryo. Two arise from the inner cellmass of the blastocyst and are continuous with splanchnopleure of the embryo; these two membranesare vascular. The four fetal membranes are:

1. Chorion — from trophoblast, forms the outer boundary of the entire conceptus.2. Amnion — from trophoblast, is formed by folds of chorion is domestic animals (in humans,

amnion forms by caviation deep to a persistent trophoblast). The amnion encloses the embryo within a fluid-filled amnionic cavity.

3. Allantois — from the inner cell mass, develops as an outgrowth of hindgut splanchno-pleure. The allantois grows to fill the entire extra-embryonic coelom, with fluid-filled allantoiccavity. The outer surface of allantois binds to the inner surface of chorion and the outer surface ofamnion. The allantois is highly vascular and provides the functional vessels of the placenta, viaumbilical vessels.

4. Yolk sac — from the inner cell mass, develops early (with hypoblast formation) and iscontinuous with midgut splanchnopleure. Supplied by vitelline vessels, yolk sac is most important inegg laying vertebrates. It forms an early temporary placenta in the horse and dog.

Note: Embryonic development is the result of interplay between genomic and localenvironmental factors. Each organ system has a critical period during develop-ment when it is most sensitive to external agents that produce birth defects.

amnion

somatopleure

splanchnopleure

gut

yolk sac

allantoischorion

coelom

embryo

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chorion(somatopleure)

amnion(somatopleure)

vitelline membrane(splanchnopleure)

allantois(splanchnopleure)embryonic

coelom

extra-embryonic coelom(lined by mesoderm)

yolksac

anllantoiccavity

amnionic cavity

hindgut

heart

branchialarch

posteriorneuropore

headprocess tail

processheart

umbilicalstalk

somites

umbilicalstalk

somites

otic placode

optic cup

heartaortic arch

pharyngeal pouch

notochord

allantois

yolk sac

stomach

hindgut

ventral aorta

dorsal aortacranialcardinal

vein

caudalcardinal vein

umbilicalvein

allantoic cavity

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Porcine Chorionic Surface(folds; diffuse placental contact)

Equine Chorionic Surface(microcotyledons)

Bovine Chorionic Surface(rows of cotyledons)

Carnivore Chorionic Surface(zonary placental contact)

Human/Rodent Chorionic Surface(discoid placental contact)

Fetal Components of Placentae

marginalhematoma

cervical star(region over cervix)ne

crot

ic t

ip(c

horio

n w

ithou

t al

lant

ois)

marginalhematoma

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Musculo-Skeletal System(Trunk, Limbs, and Head)

General Statements:Bilaterally, paraxial mesoderm gives rise

to somites and somitomeres. (Somitomeres developrostral to the notochord in the head. They are smaller andless distinctly organized that somites, but otherwise likesomites.) The mesoderm of each somite differenti-ates into three regions:

— dermatome (lateral) which formsdermis of the skin

— sclerotome (medial) forms most of theaxial skeleton (vertebrae, ribs, and base of the skull).

— myotome (middle) forms skeletalmusculature. Individual adult muscles are produced by merger of adjacent myotomes.

Nerves make early connections with adjacent myotomes and dermatomes, establishing asegmental innervation pattern. As myotome/dermatome cells migrate to assume adult positions, thesegmental nerve supply must follow along to maintain its connection with the innervation target(e.g., recurrent laryngeal & phrenic nerves travel long distances because their targets migrated).

Skin. Consists of dermis and epidermis.Epidermis, including hair follicles & glands, is derived from ectoderm. Neural crest cells

migrate into epidermis and become melanocytes. (Other neural crest cells become tactile disc receptors.)

Dermis arises from mesoderm (dermatomes of somites). Each dermatome forms a continu-ous area of skin innervated by one spinal nerve. Because adjacent dermatomes overlap, a locus ofadult skin is formed by 2 or 3 dermatomes, and innervated by 2 or 3 spinal nerves.

Muscle. Muscles develop from mesoderm, except

for muscles of the iris which arise from optic cup ectoderm. Cardiacand smooth muscles originate from splanchnic mesoderm.

All skeletal muscle is derived from paraxial meso-derm, which forms somites and, in the rostral region of thehead, somitomeres. Mesodermal cells of the myotomeregion of each somite/somitomere differentiate into myo-blasts which fuse to form multinucleate muscle cells thatsynthesize myosin & actin and appear striated.

Muscle development requires innervation. Also,muscles and tendons must be under tension (stretched by growing bone) in order to grow to properlengths.

Note: Each anatomical muscle is genetically allocated a specific number of myoblasts that isdetermined by the time of birth. Thereafter, muscle cell growth is due solely to cellularhypertrophy. Regeneration (hyperplasia) of adult muscle cells does not occur.

Mesoderm Regions

ectoderm

endoderm

neural tube

neural crest

aorta

coelom

somite: dermatome

sclerotomemyotome

intermediate mesoderm

somatic mesoderm

splanchnic mesoderm

notochord

head

heart limbbudeye

somitomeresin

pharyngeal arches

somites

Somites & Somitomeres

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Bone. Bones originate from paraxial mesoderm (endochondral axial skeleton fromsclerotomes), somatic mesoderm (endochondral appendicular skeleton), or ectomesenchyme (in-tramembranous bones of the calvaria and face from neural crest). Ligaments, tendons, and muscle-related

connective tissue originate from local mesenchyme or ectomesenchyme.

Thus, most bones are formed endochondrally (ossification of a cartilage model), but bones ofthe calvaria (top of the skull) and the face are formed intramembranously (ectomesenchyme cellsbecome osteoblasts directly rather than becoming chondroblasts).

Endochondral bone formation:— mesenchyme undergoes condensation and some cells differentiate into chondroblasts— chondroblasts secrete matrix to produce a cartilage model of the future bone; the model is

surrounded by perichondral fibrous tissue— the diaphysis of the cartilage model undergoes ossification first; epiphyseal ossification

occurs later; physis ossification is postponed until bones stop growing in length.— overall bone shape is genetically determined; surface irregularities of bone are acquired

due to localized tension (stress) produced by ligaments and tendons.

Joints. Condensation of mesenchyme produces an interzone region within perichondraltissue connecting adjacent cartilage models of bones. According to the nature of the future joint, theinterzone becomes fibrous connective tissue,or fibrocartilage, or a synovial cavity.

Synovial joints form as follows:— mesenchyme at the center of the

interzone undergoes cavitation and the tissuebordering the cavity become synovial mem-brane; uneven expansion of the synovialcavity creates synovial folds (the interzone

mesenchyme also forms intra-articular ligaments and tendons where these are present);— perichondral tissue surrounding the interzone becomes joint capsule and localized thick-

enings of the joint capsule forms ligaments.

Note: Muscle activity is essential for proper synovial joint development after thejoint cavity develops. Joints must move during in utero and postnatal develop-

ment to prevent ankylosis (fixed/frozen joint).

Regional Specifics

Trunk Region:Skeletal musculature is formed by somite myotomes which fuse to form broad muscles that

are segmentally innervated (each myotome brings its own innervation as it merges with adjacentmyotomes). Myotome accumulations segregate into a dorsal mass (epimere) innervated by dorsalbranches of spinal nerves and a ventral mass (hypomere) innervated by ventral branches of spinalnerves. The epimere becomes epaxial muscles and the hypomere becomes hypaxial muscles.

Sclerotomes give rise to vertebrae and ribs. The sternum develops from chondrification/ossification of

somatic mesenchyme of the ventral thorax.

Synovial Joint Development

perichondral layer

cartilage (bone)

interzone ligament

cavitation

fibrous capsule

synovialmembrane

synovialcavity

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Formation of Vertebrae and Ribs:— sclerotome regions of somites become a continuous

mass surrounding the notochord, such that the original somitesegmentation is lost

— the solid mass differentiates into diffuse & dense regionsin craniocaudal sequence

— diffuse regions combine with the dense regions of theadjacent (caudal) somite to produce cartilage models of vertebrae

— between vertebrae (intervertebral disc regions) sclero-tome mesenchyme forms annulus fibrous and notochord formsnucleus pulposus (notochord degenerates in the region of thevertebral body)

— ribs develop as processes of thoracic vertebrae.

Note: As a result of re-segmentation, vertebrae are shiftedrelative to other segmental structures (see next page).Consequently, muscles span adjacent vertebrae; spinalnerves traverse intervertebral foramina (located dorsalto intervertebral discs); and embryonic intersegmental arteries

become spinal branches that run along side vertebral bodies.

Vertebral anomalies include: stenosis of the vertebral canal; mal-articulation; hemivertebra; and spinal bifida (absent vertebral arch). Thenotochord, neural tube, and neural crest all play a role directing somite differen-tiation and vertebral segmentation (formation).

Note: The dens originates as the body of vertebra C1, but it fuses

with vertebra C2.

Limbs:

Limbs grow outward from body wall somatopleure as limbbuds. Bone, cartilage, and related connective tissue arise fromsomatic mesoderm of the limb bud. Dermis and skeletal musclecome from dermatome and myotome migrations into the limb.

Limb Morphogenesis:— a limb begins as a limb field (an area of somatopleure

committed to forming a limb)— next, a limb bud is produced by localized proliferation &

condensation of mesenchyme, covered by ectoderm— regions of the limb develop in proximodistal order as the

limb bud elongates (the shoulder/hip appears first, the manus/pes isthe last to be added)

— the distal end of the limb bud (footplate) is flattened likea paddle and ectoderm along its outer margin thickens to form anapical ridge (the ridge is induced to form by underlying mesoderm and it

induces the mesoderm to continue growing and differentiating into a limb)

dorsal branch

ventralbranch

epaxialmuscles

hypaxialmuscles

coelom

spinalnerve

gut

Myotome Segregation

L-2

L-3

L-4

Canine Dermatomes

18

caudal

sclerotome

spinal n.

neural segmentstube

cranial

myotome

continuous mass

dense diffuse

vertebra

intervertebral disc

muscle

neural tubedorsal root

ectoderm

notochord

somite

sclerotome myotome

dermatome

ossificationspinous process

ribtubercle

ribhead

vertebralcanal

transverse process

vertebralbody notochord

Sclerotomes to Vertebrae

19

— mechanically, limb growth consists of:- elongation of a dorsoventrally flattened limb bud- ventroflexion of the distal half of the limb (ventral now faces medially)- pronation of the distal half (previous medial surface now becomes caudal)

— separate digits are produced by interdigital necrotic zones (species with

fewer digits undergo further degeneration and/or fusion of digits);— local mesenchyme condenses to form cartilage models of limb bones— myotome cells migrate into the base of the limb forming extensor &

flexor muscle masses that subsequently segregate into individual muscles;— vessels and nerves grow into the limb.

Clinical considerations:Achondroplasia (dwarfism; Dachshund) — inherited, systemic prema-

ture ossification of physes of extremities.Arthrogryposis [Gr. gryposis = crooked] can result from malformed

joints, denervation, abnormal muscle tension, or impaired mobility in utero.Polydactyly (extra digits); syndactyly (fused digits); brachydactyly

(stumpy digits Gr. dactylos = digit]Amelia (no limb); meromelia (absence of part of limb); micromelia

(small limb Gr. melos = limb]Note: phocomelia (seal limb) = absence of proximal segment(s) of limb

was a consequence of pregnant women taking thalidomide in 1950s.

Head Region:The head consists of a cranium, which contains the brain within a cranial cavity, and a face.

The face develops separately from the frontonasal process and first pharyngeal arch. Since the faceand cranium have different embryonic origins they can be independently influenced genetically (e.g.,in the case of brachycephalic breeds) or by teratogens.

Skull. Bones of the base of the cranium develop endochondrally; the relatively flat bones thatcomprise the calvaria (roof of the cranium) and the face develop intramembranously.

The endochondral bones are formed from sclerotomes of somitomers and the first four somites(occipital somites).

The intramembranous bones arise from ectomesenchyme (mesenchyme derived from neuralcrest), which gives rise to cartilage, bone, and connective tissue of the face and dorsal head. Intramem-branous bones articulate by means of fibrous joints called sutures. Widened suture areas, at the corners of growing bones,are called fontanels. Sutures and fontanels allow bony plates to overlap one another during birth.

Manus/PesDevelopment

foot plate

cell death

digit

face(intramembranous)

base of cranium (endochondral )

Regions of the Skull

calvaria of cranium(intramembranous )

20

Note: Auditory ossicles arise endochondrally from branchial arches I (malleus & incus) and II (stapes).

Muscles. Muscles of the head arise from somitomeres (seven) and somites (four occipital

somites).Somitomere myotomes migrate to the orbit (two give rise eye muscles) or to pharyngeal

arches (becoming muscles of mastication and facial expression).Somite myotomes become tongue and neck muscles and migrate to pharyngeal arches IV-VI

(pharyngeal, laryngeal & esophageal mm.).

Cranial nerves establish early connections with adjacent somitomeres & somites and accom-pany them to definitive muscle sites. Pharyngeal arches are innervated by specific cranial nerves(I=trigeminal; II=facial; III=glossopharyngeal; IV-VI=vagus).

Pharyngeal (Branchial) Arch Summary:Ectomesenchyme migrates to pharyngeal arches to form connective tissue, cartilage and

bone. Somitomere/somite myotomes migrate into the arches and give rise to skeletal muscle. Eacharch is innervated by a particular cranial nerve.

First arch. (innervated by cranial nerve V)— jaw bones (mandible & maxilla); also, ossicles of the middle ear (incus & stapes)— muscles of mastication, plus rostral digastricus, mylohyoid, & tensor tympani mm.

Second arch: (innervated by cranial nerve VII)— hyoid bones & stapes (ossicle of the middle ear)— muscles of facial expression, including caudal digastricus & stapedius mm.

Third arch: (innervated by cranial nerve IX)— hyoid bones— one pharyngeal muscle (stylopharyngeus mm.)

Arches IV through VI: (innervated by cranial nerve X)— laryngeal cartilages— pharyngeal mm & cricothyroid m — innervated by cranial branch of X— intrinsic laryngeal mm — innervated by recurrent laryngeal n. of X

21

Formation of Body (Serous) CavitiesSerous cavities are cavities lined by serous membrane (mesothelium). In the adult, serous

cavities are: the pericardial cavity, two pleural cavities, and the peritoneal cavity (including vaginalcavity extensions of the peritoneal cavity).

Acquiring a three-dimensional understanding of howserous cavities are formed is a challenging exercise. Serouscavity formation may be summarized as follows:

• all of the serous cavities develop from a commonembryonic coelom and thus the cavities are continuous untilpartitions develop to separate them;

• the individual serous cavities are formed by inwardgrowth of tissue folds from the body wall (partitions) and byoutgrowth of coelomic cavity into the body wall (excavation).

Coelom Development:During gastrulation, the space between ectoderm and

endoderm (and between trophoblast and hypoblast) is filled byinflow of primary mesenchyme that becomes mesoderm.Cavitation occurs in lateral mesoderm, establishing thecoelom bounded by somatopleure and splanchnopleure.

As head and tail processes develop and lateral bodyfolds merge medially (except at the umbilicus), embryonic andextra-embryonic compartments of the coelomcan be differentiated. The former becomes theserous cavities, the latter is filled by allantoicfetal membrane.

Formation of the head process bringsthe heart and pericardial coelom within theembryo, positioned ventral to the foregut.Right and left sides of the embryonic coelomare separated by gut and by dorsal and ventralmesenteries, the latter fails to develop caudalto the midgut.

Thus, the embryonic coelom featuresan anterior-ventral pericardial compartment, acaudal peritoneal compartment, and bilateralpleural compartments (channels) connectingthe pericardial and peritoneal compartments. Mesoderm lining the coelom forms mesothelium.

Separation of Peritoneal and Pleural Cavities:In the adult, peritoneal and pleural cavities are separated by the diaphragm. The diaphragm is

formed by a septum transversum, paired pleuroperitoneal folds, and somatic mesoderm. Diaphrag-matic musculature is derived from somites in the cervical region (C

5, 6, 7), where the diaphragm is

initially formed.

Mesoderm = somite = intermediate = lateral

neural tubenotochord

foregut

mesentery

yolksac

embryoniccoelom

extra-embryoniccoelom

somatopleuresplanchnopleure

LateralBody Folds

Coelom(Longitudinal View)

pericardium

coelom

ectoderm

endoderm

embryo

extrembryoniccoelom

embryoniccoelom

foregut hindgut

yolksac

22

Pleural Cavity FormationEarly Late

pleuralcoelom

pericardialcoelom

heart

esophagusdorsal aorta

aorta

limbneural tube

pleuro-pericardialfold

body wall

fibrouspericardium

lung

vertebra

pleural cavity

lung budmediastinum

preicardial sac

Diaphragm Formation(Caudal View)

septumtransversum

pleuro-peritoneal

fold

degeneratingmesonephros

vertebra

aorta

esophagus

caudalvenacava

centraltendon

crus ofdiaphragm

diaphragmmuscle

pleuro-peritoneal

canal

Details of diaphragm formation include:

— the septum transversum originates as mesoderm in front of theheart; as the heart shifts ventral to the foregut, the septum becomes incorpo-rated into the ventral body wall and ventral mesentery caudal to the heart; itgrows dorsally and forms a transverse partition ventral to the level of the gut

— dorsal to the gut, bilateral pleuroperitoneal folds grow mediallyand meet at the dorsal mesentery

— subsequent growth of the pleural cavity into somatic mesoderm(mesenchyme) will result in body wall mesoderm forming the marginalregions of the diaphragm (diaphragm musculature).

Separation of Pericardial and Pleural Cavities:In the adult, pericardial and pleural cavities are separated

by fibrous pericardium.Originally in the embryo, the pericardial coelomic cavity

communicated with two dorsally positioned pleural cavities(canals). Subsequently, the cavities become partitioned by pairedpleuropericardial folds and then somatic mesoderm. Details ofthe separation include:

— bilateral pleuropericardial folds (membranes), which accompanycommon cardinal veins as they join the heart, converge medially to unite withthe mediastinum (ventral mesentery) and partition the ventral pericardialcavity from the dorsal pleural canals;

— subsequent ventrolateral growth of the pleural cavities into thebody wall incorporates somatic mesoderm (mesenchyme) into the futurefibrous pericardium.

NOTE: Mediastinum is formed initially by dorsal and ventralmesenteries of the esophagus.

Growth of Pleural Cavities:Initially the pleural cavities are small canals into which the lung buds project. As the lungs

grow, the pleural cavities enlarge and appear to carve into the body wall (into somatic mesoderm/mesenchyme). As a result, somatic mesoderm forms partitions (fibrous pericardium and diaphragm)that wall off the pleural cavities.

23

Cardiovascular SystemNote: The cardiovascular system develops early, enabling the embryo to grow beyond the short dis-

tances over which diffusion is efficient for transferring O2, CO2, and cellular nutrients &wastes.

Heart:From a simple tube, the heart undergoes differential growth into a four chambered structure

while it is pumping blood throughout the embryo and into extra-embryonic membranes. The heart

initiates a peristaltic pumping action by about 18 days in the dog.

Formation of a Tubular Heart:The first evidence of heart

development is bilateral vesselformation within the cardiogenicplate, which is splanchnic mesodermsituated anterior and lateral to theembryo. As the head process growsupward and outward, bilateralendocardial tubes meet at the mid-line and fuse into a single endocar-dial tube. Splanchnic mesodermsurrounding the tube forms cardiacmuscle cells.

Primitive Heart Regions:Differential growth of the endocardial tube establishes five primitive heart regions:

1] Truncus arteriosus — the output region ofthe heart. It will develop into the ascendingaorta and pulmonary trunk.

2] Bulbus cordis — a bulb-shaped regiondestined to become part of the right ventricle(conus arteriosus).

3] Ventricle — an enlargement destined tobecome the left ventricle.

4] Atrium — a region that will expand tobecome both right and left auricles.

5] Sinus venosus — a paired region intowhich veins drain. The left sinus venosusbecomes the coronary sinus; the right isincorporated into the wall of the right atrium.

Forming a Four-Chambered Heart:A] The endocardial tube lengthens and loops on itself—this puts the bulbus cordis (right ventricle)

beside the ventricle (left ventricle).

Midline FusionTubular Heart

truncusarteriosus

bulbuscordus

ventricle

atrium

sinusvenosus

L R L

R

amnionic cavity

ectodermembryo

yolk sac endodermmesoderm

cardiogenicplate

embryo

yolk sac

heart

24

B] Venous return is shiftedto the right side. The right sinusvenosus becomes enlarged andincorporated into the future rightatrium. The smaller, left sinusvenosus merges into the future rightatrium as coronary sinus.

The atrium expands and overliesthe interventricular opening, creating acommon atrioventricular opening (canal).A constriction, the future coronary groove,separates atria and future ventricles at thelevel of the atrioventricular opening.

C] The common atrio-ventricular opening is partitioned into right and left A-V openings bygrowth of endocardial cushions. Subsequently, ventral growth of the cushions produces a septumthat closes the interven-tricular foramen (theoriginal opening betweenthe bulbus cordis andventricle).

Incomplete closure ofthe interventricular septum(ventricular septal defect)results in blood flow from theleft to the right ventricle and anassociated murmur. Largedefects produce clinical signsof cardiac insufficiency.

D] The right andleft ventricles are formed by ventral growth and excavation of the bulbus cordis and ventricle,respectively. An interventricular septum, atrioventricular valves, chordae tendineae, papillarymuscles, and irregularities of the internal ventricular wall are all sculptured by selective excavationof ventricular wall tissue.

E] Right and left atria are established by formation of an interatrial septum. Septum forma-tion is complicated by the need, until birth, for a patent septum that allows blood to flow from theright atrium to the left. The septal opening iscalled the foramen ovale.

Two septae and three foramina are involved individing the atria:

Interatrial Septum 1 grows from the dorsal wallof the atrium toward the endocardial cushions at theatrioventricular canal. The pre-existing Foramen 1 isobliterated as Septum 1 meets the endocardial cushions.

Foramen 2 develops by fenestration of thedorsocranial region of Septum 1.

Interatrial Septum 2 grows from the cranialwall of the right atrium toward the caudal wall. Theseptum remains incomplete and its free edge forms theboundary of an opening called the Foramen Ovale.

Sagittal Section

Endocardial Tube

sinus venosus

commonatrioventricular

openingventricle

bulbuscordis

atrium

truncus arteriosus

cranial

caudal

bulbuscordis

ventricle

atriumsinus venosus

VentricleDevelopment

atrium

rightventricle left

ventricle

atrium

interventricular: foramen septum

endocardialcushiontruncus

arteriosus

bulbuscordis

ventricle

secondary septum

secondaryforamen

foramenovale

primary septum(valve of f.ovale)

rightatrium

sinuatrialopening

Blood Flow Through Foramen Ovale

path ofblood flow

25

NOTE: As long as blood pressure in the right atrium exceeds that of the leftatrium, blood enters the Foramen Ovale, flows between the two septae andexits through Foramen-2. When, at birth, pressure is equal in the two atria,Septum-1 is forced against the Foramen Ovale, acting as a valve to close theforamen and preclude direct blood flow between the atria. An atrial septal defect is not a serious developmental anomaly as long as pressure is

approximately equal in the two atria, which is normally the case.

F] Aorta and pulmonary trunk are formedby partition of the truncus arteriosus (and adjacent

bulbus cordis). In a spiral pattern, ridges appear alongthe lumen wall, grow inward and merge creating aspiral septum. As a result, the aorta and pulmonarytrunk spiral around one another. Failure of the septumto spiral leaves the aorta connected to the right ventricle andthe pulmonary trunk to the left ventricle—a fatal flaw.

Aortic and pulmonary semilunar valves areformed like atrioventricular valves, by selectiveerosion of cardiac/vessel wall. Improper valve sculptur-ing will produce valvular insufficiency in the case of exces-sive erosion or vessel stenosis (narrow lumen) in cases of notenough erosion.

Note: Neural crest cellsmigrate to theregion of thetruncus arteriosusand direct itspartitioning by thespiral septum.Ablation of theneural crest resultsin anomalies of thegreat vessels.

Tetralogy of Fallot:This is a cardiac anomaly that occurs in number of species, including humans. It involves a combination of fourdefects related to a defective spiral septum formation in the truncus arteriosus & bulbus cordis:

• ventricular septal defect;• stenosis of the pulmonary trunk;• enlarged aorta that overrides the right ventricle (dextroposition of the aorta); and• hypertrophy of the right ventricle, secondary to communication with the high pressure left ventricle.

Note: Early in development, blood islands form in splanchnic mesoderm of the yolk sac andallantois. Angiogenesis (vessel formation) occurs when island vesicles coalesce to formchannels. Subsequently, hematopoiesis (blood cell formation) occurs in the liver and spleenand later in the bone marrow. The transition from fetal to adult circulation involves newvessel formation, vessel merger, and vessel degeneration.

Spiral Arrangement of theAorta & Pulmonary Trunk

caudal vena cava

aorta

pulmonarytrunk

rightatrium

leftatrium

rightventricle

leftventricle

Development of semilunar valves by excavation

aorta or pulmonary trunk semilunarcusp

flowfromheart

vessel wall excavation

26

rightintersegmental aa.

Early Arteries & Veins

yolk sacvessels

allantoicvessels

umbilical a.

umbilical v.

vitelline a.

vitelline v.aorticarch

ventralaorta

dorsalaorta

HEART

commoncardinal v.

cranialcardinal v.

caudalcardinal v. iliac

branch

Arteries:

Dorsal and Ventral Aortae:The embryo develops paired ventral and dorsal aortae. The two ventral aortae receive blood

from the truncus arteriosus. Bilaterally, ventral and dorsal aortae are connected by a series of sixaortic arches. Each aortic arch is situated within a pharyngeal (branchial) arch.

Paired ventral aortae fuse to form the brachiocephalic trunk. Caudal to the aortic arches, thepaired dorsal aortae merge to form a single descending aorta, as found in the adult. The aorta gives offdorsal, lateral, and ventral branches, some of which persist asadult vessels. Aortic arches become carotid, subclavian, arch ofthe aorta, and pulmonary arteries.

Disposition of Aortic Arches:Only the third, fourth, and sixth aortic arches

become adult vessels. The first two arches degenerate andthe fifth arch is rudimentary or absent.

Each third aortic arch becomes an internalcarotid artery. The dorsal aorta degenerates between the thirdand fourth aortic arches. Consequently, the third arch suppliesthe head and the fourth arch supplies the more caudal regions.The external carotid artery buds from the third arch. Proximal tothis the third arch forms common carotid artery.

The left fourth aortic arch becomes the adultarch of the aorta. The right fourth aortic arch becomes theproximal part of the right subclavian artery as the distal connec-tion between the arch and the dorsal aorta normally degenerates.Persistence of a connection between the fourth aortic arch andthe descending aorta results in compression of the esophagus,accompanied difficult swallowing and an enlarged esophaguscranial to the compression.

The proximal part of each sixth aortic arch becomes a pulmonary artery. The distal part of thearch degenerates on the right side but persists as ductus arteriosus on the left side.

Aortic Arches 3, 4, 6(Dorsal View)

aorticarch 3

aorticarch 4

aorticarch 6

commoncarotid a.

internalcarotid a.

externalcarotid a.

dorsalaorta

degeneratingdorsalaorta

ductusarteriosus

pulmonary a. right 7thintersegmental a.left 7th

intersegmental a.

descending aorta

degeneratingright dorsal aorta

27

Note: The ductus arteriosus shunts blood from the pulmonary trunk to the aorta.The shunt allows the right ventricle to be exercised in the face of limitedcapacity of the lungs to accept blood. At birth, constriction of the ductusarteriosus abruptly shifts pulmonary trunk output to the lungs. Eventually, aligamentum arteriosum replaces the constricted ductus arteriosus.A persistent ductus arteriosus results in a continuous murmur during both systole anddiastole.

Subclavian & Vertebral arteries:Each dorsal aorta gives off intersegmental arteries that pass dorsally between somites. The seventh cervical

intersegmental artery becomes the distal subclavian artery bilaterally.Intersegmental arteries cranial to the seventh to form the vertebral artery (by degenerating proximally and

anastomosing distally). Intersegmental arteries caudal to the seventh cervical become intercostal and lumbar arteries.As the heart shifts caudally from the neck to the thoracic cavity, positions of aortic arch arteries are changed

relative to the heart. In particular the subclavian arteries becomes transposed from a position caudal to the heart to acranial position.

Branches of Dorsal Aortae:Right and left vitelline arteries arise from right and left dorsal aortae, respectively, to supply the yolk sac. The

right vitelline artery becomes the cranial mesenteric artery. The left vitelline artery normally degenerates. Incompletedegeneration of the left vitelline artery can result in a fibrous band that may cause colic by entrapping a segment ofintestines.

Each dorsal aorta terminates in an umbilical artery that supplies blood to the allantois. In the adult, umbilicalarteries persist proximal to the urinary bladder and degenerate distal to the bladder. External and internal iliac arteriesdevelop as outgrowths of the umbilical artery.

Veins:

The sinus venosus receives vitelline veins which drain the yolk sac, umbilical veins whichdrain the allantois, and cardinal veins which drain the embryo. The transition from embryonic toadult venous patterns involves the formation of new veins, anastomoses between veins, and theselective degeneration of embryonic segments.

Note: Recall that venous return is shiftedto the right side so that the rightsinus venosus is incorporated intothe right atrium while the left sinusvenosus is reduced and becomescoronary sinus.

Cranial Vena Cava Formation:Each cranial cardinal vein becomes the adult internal

jugular vein. The much larger external jugular and subcla-vian veins arise by budding from the cranial cardinal vein.

An anastomotic vein develops and runs from left toright cranial cardinal veins, shifting venous return to the rightside and becoming left brachiocephalic vein. The caudalsegment of right cranial cardinal vein along with the rightcommon cardinal vein becomes the cranial vena cava.(Failure of the anastomotic vein to develop results in a doublecranial vena cava, the typical condition in rats and mice.)

Cranial Vena CavaDevelopment (Dorsal View)

coronary sinus

caudalvena cava

cranialvena cava

R. sub-calavian

v.

external jugular v.

brachio- cephalic vv.

L. sub-calavian

v.

anastomoticbranch

right atrium

degeneratedleft cranial cardial v.

28

Caudal Vena Cava and Azygos Vein:Each caudal cardinal vein gives rise to supra-cardinal and sub-cardinal veins with extensive anastomoses among

all of the veins. These venous networks, located in intermediate mesoderm, supply embryonic kidneys and gonads.Selective segments of particularly the right subcardinal venous network, including an anastomosis with the

proximal end of the right vitelline vein form the caudal vena cava.The azygos vein develops from the supracardinal vein as well as the caudal and common cardinal veins of the

right side (dog, cat, horse) or the left side (pig) or both sides (ruminants). The azygos vein will drain into the cranial venacava (or right atrium) on the right side and into the coronary sinus on the left side.

Portal Vein and Ductus Venosus:Proximally, vitelline veins form liver

sinusoids as the developing liver surrounds theveins. Anastomoses develop between right and leftvitelline veins, and enlargement or atrophy ofselective anastomoses and right/left segments ofvitelline veins gives rise to the portal vein.

Umbilical veins, also engulfed by thedeveloping liver, contribute to the formation ofliver sinusoids. Within the embryo, the rightumbilical vein atrophies and the left conveysplacental blood to the liver. Within the liver, ashunt, the ductus venosus, develops between theleft umbilical vein and the right hepatic vein whichdrains into the caudal vena cava.

Postnatally, the left umbilical vein becomes theround ligament of the liver located in the free edge of thefalciform ligament.

Note: Because a fetus is not eating and because the placenta is able todetoxify blood, it is desirable for venous return to bypass fetal liver sinusoidsvia the ductus venosus, a shunt that diverts blood to systemic veins.

Postnatally, however, a continuing portosystemic shunt allows toxicdigestive products to bypass the liver. These toxic agents typically affect thebrain resulting in neurologic disorders at some time during life.

A portosystemic shunt can be the result of a persistent ductus venosusor a developmental error that results in anastomosis between the portal veinand the caudal vena cava or the azygos vein. Since adult veins are establishedby patching together parts of embryonic veins, it is not surprising that mis-connections arise from time to time.

Vitelline & Umbilical Veins(Ventral View)

heart atriumsinus

venosus

caudalcardinal v.

commoncardianl v.

cranial cardinal v.

liversinusoids

rightumbilical

v.

vitelline v.

FOREGUT

leftumbilical v.

LIVER

degenerating segment

29

Lymphatics:

Lymph vessel formation is similar to blood angiogenesis. Lymphatics begin as lymph sacs inthree regions: jugular (near brachiocephalic veins); cranial abdominal (future cysterna chyla); and iliac region.Lymphatic vessels (ducts) form as outgrowths of the sacs.

Lymph nodes are produced by localized mesoder-mal invaginations that partition the vessel lumen intosinusoids. The mesoderm develops a reticular framework withinwhich lymphocytes accumulate. The spleen and hemal nodes (in

ruminants) develop similar to the way lymph nodes develop.

At birth...

Stretching umbilical arteries resultsin arterial constriction and reduced fetalblood flow to the placenta. Reduced venousreturn through the (left) umbilical vein andductus venosus allows the latter to gradu-ally close (over a period of days).

Increased oxygen concentration inblood triggers constriction of the ductus ar-teriosus which, over time, is gradually con-verted to a fibrous structure, the ligamen-tum arteriosum. The increased blood flowto the lungs and then to the left atrium equal-izes pressure in the two atria which resultsin closure of the foramen ovale.

ductus arteriosus

Three In-Utero Adjustments

foramen ovale

ductusvenosus

aortic arch

pulmonary trunk

caudal vena cava

liver

umbilical v.

portal v.

aorta

umbilical aa.

Latrium

Ratrium

sinusoid

mesenchyme

lymph duct lumen

mesodermalinvagination

Lymph Node Formation

30

Digestive SystemNOTE: The digestive system consists of the: mouth (oral cavity); pharynx; esophagus; stomach; small

intestines; colon and cecum; rectum; anal canal; and the liver, pancreas, and salivary glands.

Development of a head process and tail process, includingthe ventral merger of lateral body folds, transforms splanchno-pleure into a foregut and a hindgut, leaving a midgut region that iscontinuous with the yolk sac.

NOTE: Foregut becomes pharynx, esophagus, stomach, cranial duode-num, and liver and pancreas. Midgut becomes the remaining smallintestines, cecum, ascending colon, and part of the transversecolon. Hindgut becomes transverse and descending colon and acloaca which forms the rectum and most of the anal canal. In the abdomen, derivatives of the foregut, midgut, and hindgutare those structures supplied by the celiac, cranial mesenteric, andcaudal mesenteric arteries, respectively.

Endoderm gives rise to the epithelial lining of the digestive tract, while splanchnic mesodermforms connective tissue and smooth muscle components of the digestive tract wall; except thatectoderm forms the epithelial lining of the proctodeum (caudal end of anal canal) and stomadeum(mouth & salivary glands — parotid, zygomatic, labial & buccal).

Pharynx...The adult pharynx is a

common respiratory-digestivechamber. Initially, the pharynxis bounded cranially by anoropharyngeal membrane. Themembrane degenerates early,allowing the pharynx to com-municate with the oral andnasal cavities, and enablingmigration of tongue muscula-ture into the oral cavity.

Although the adult pharynx has a smooth wall, pharyngeal pouchesappear during development. The pouches give rise to several structures, twoof which retain continuity with the pharyngeal cavity (auditory tube andfossa of the palatine tonsil). A midline evagination of the floor of the phar-ynx gives rise to the larynx, trachea and lungs.

Esophagus...The esophagus develops from foregut, caudal to the pharynx. Its principal morphogenic

development is elongation.Skeletal muscle associated with esophagus & pharynx is derived from somites that migrate to

the branchial arches IV-VI (innervation is from vagus nerve). Esophagus is coated by skeletal muscle throughout its

length (dog, ruminants), to the diaphragm (pig), to the mid-thorax (cat, horse, human), or not at all (avian).

pharynx

cloaca

allantois

foregut hindgutmidgut

yolksac

stomach

pharyngealpouches

trachea

midgut

diverticulumcecum

allantois

cloaca

pancreas

gallbladder

liver

AlimentaryCanal

31

Stomach (simple stomach)...Most domestic mammals have a simple stomach (in contrast, ruminants have a complex

stomach with multiple compartments). The simple stomach develops from a tubular segment offoregut that undergoes the following morphogenic changes:

• growth is more rapid dorsally than it is ventrally; the tube becomes convex dorsally (thefuture greater curvature) and concave ventrally (future lesser curvature);

• the tube rotates 90° to the left (dorsal faces left & ventral faces right);• the long axis becomes transverse as growth of the liver pushes the cranial end of the

stomach to the left side (the greater curvature drops ventrally when the stomach is filled);— growth along the cranial aspect of the greater curvature is greater than along

the caudal aspect — this produces afundus region (to the left);

— endoderm, which forms the epitheliallining of the stomach, differentiatesinto cells types that vary regionallyamong species.

Ruminant stomach...The ruminant stomach consists of three compart-

ments lined by stratified squamous epithelium (rumen,reticulum, and omasum) and one glandular compart-ment (abomasum). The early development of theruminant stomach is the same as the simple stomach.

The rumen develops as an expansion of the fundus,and a caudoventral pocket of the developing rumenforms the reticulum. The omasum develops as a bulgealong the lesser curvature. The rest of the stomachbecomes abomasum. Later in development the rumenis “flipped” caudally so it comes to lay on top of theabomasum with the reticulum situated cranially.

LEFT RIGHTDORSAL VIEWSIMPLE STOMACH DEVELOPMENT

RotatedLeft

Long AxisTransverse

esophagusesophagus

lessercurvature

duodenum

duodenum

stomachfundus

greater curvature

stomach

✠

✠

dors

al b

orde

r

rumen

omasum

reticulum

abomasum

rumen(ventral sac)

omasum

reticulumabomasum

rumen (dorsal sac)

esophagus

esophagus

duodenum

duodenum

RumenDevelopment

32

Intestinal tract...

NOTE. The intestinal tract consists of: duodenum (descending & ascending), jejunum, ileum, colon (ascending,transverse, & descending). cecum (diverticulum at the beginning of the colon), rectum, and anal canal.

In addition to elongation, the following morphogenic events occur:— elongation of the midgut (where the yolk sac is attached) causes the midgut to form a loop

that herniates into the coelom of the umbilical stalk;— the loop rotates approximately 360° around the cranial mesenteric artery (former right

vitelline a.), the rotation is clockwise as viewed dorsally (freedom to rotate is the result

of lost yolk sac attachment and elongation of the cranial limb of the loop);— the caudal limb of the loop develops a diverticulum, the future cecum, and the loop

returns to the embryonic coelom (abdominal cavity).

NOTE:The intestinal tract and esophagus normally become atretic (oc-

cluded lumen) during development as a result of epithelial proliferation.The atresia is temporary. Recanalization occurs by formation of vacuolesand coalescence of the vacuoles to form the ultimate lumen. Persistentatresia (failure to re-canalize) or stenosis (narrow lumen) is a congenitalanomaly that can occur at localized sites anywhere along the esophagus orintestines.

Failure of the yolk sac to detach from the midgut (jejunum) canresult in a diverticulum of the jejunum, a fistulous (hollow) cord to theumbilicus, or a fibrous connection between the jejunum and umbilicus.Each of these can be a source of colic.

Additional intestinal events in some species...a secondary loop (of ascending colon) forms distal to the cecum (see following illustration): • in pig and ruminant—the secondary loop coils (forming the spiral colon); • in horse—the secondary loop bends on itself; also the cecum enlarges so that the proximal colon

is incorporated within the cecum.

cranial mesenteric arterystomach

cecum

yolksac

180 degrees 360 degrees

Rotation of Gut Around Cranial Mesenteric A.

cecum

cecum

stomach

stomach

start

(left side view)

33

Cloaca...The hindgut terminates in a cloaca, i.e., a chamber that communicates with the digestive,

urinary and genital systems (the cloaca persists in adult birds, reptiles, & amphibians). The allantoisevaginates from the hindgut at the cranial end of the cloaca. The caudal wall of the cloaca, which isformed by endoderm apposed to surface ectoderm, is designated cloacal membrane.

Rectum: The rectum is formed when a mesenchymepartition (urorectal septum) divides the cloaca into dorsal andventral chambers. The dorsal chamber, which is continuouswith the hindgut, becomes the rectum and most of the analcanal. The ventral chamber, the urogenital sinus, is continu-ous with the allantois.

The urorectal septum grow caudally and divides thecloacal membrane into an anal membrane dorsally and aurogenital membrane ventrally. The membranes subsequentlydisintegrate in normal developement.

Anal canal: The cranial part of the anal canal (most of the canal) is formed with the rectum;this part of the anal canal is lined by a mucosal epithelium derived from endoderm. The caudal partof the anal canal (caudal to an anocutaneous line) is lined by stratified squamous epithelium. It formsas follows:

— tissue surrounding the analmembrane grows caudally creating a depressioncalled the proctodeum; when the anal membrane degenerates, theproctodeum becomes incorporated into the anal canal (atresia ani or intactanal membrane is a congenital anomally);

— in carnivores, lateral diverticula of proctodeum ectoderm become anal sacs.

NOTE: The urinary bladder develops from the cranial part of the urogenital sinusand the proximal end of the allantois.

urogenitalsinus

allantois

urorectalseptum

rectum

analcanal

cloacalmembrane

Cloaca Divisions

cecum

stomach

descendingcolon

descendingduodenum

ileum

jejunum

ascending colon

cranial mesenteric a.

Ascending Colon Loop(right side view)

bovine

equine

porcine

34

Liver...The liver arises as an hepatic diverticulum of endoderm from the region of foregut that will

become descending duodenum. The diverticulum gives rise to multiple branches that will become:hepatic ducts, cystic duct and the pancreatic duct.

Continued growth and branching of hepatic duct primordia form the lobes of the liver. A gallbladder develops at the end of the cystic duct. The initial part of the hepatic diverticulum from whichthe various branches arose becomes the bile duct.

The hepatic diverticulum grows within ventral mesogastrium (lesser omentum). The diverticulum temporarilypenetrates the future diaphragm (septum transversum) which contributes connective tissue to the liver. The hepaticdiverticulum originates ventrally but differential growth of the duodenal wall results in the bile duct entering the duode-num dorsally, with the pancreatic duct on the major duodenal papilla.

Pancreas...The pancreas originates as two separate endoderm diverticula, each of which elongates,

branches, and then forms acini in typical glandular fashion. One diverticulum arises ventrally as abud of the hepatic diverticulum; it forms the pancreatic duct and right lobe of the pancreas. The otherdiverticulum arises dorsally from the duodenum (minor duodenal papilla) and forms the accessorypancreatic duct and the left lobe of the pancreas.

As the right and left lobes cross one another during development, they fuse to from the bodyof the pancreas; also, the duct systems anastomose to form a common system. The endocrine (islet)cells of the pancreas also develop from the endoderm of the diverticula.

NOTE: One of the two pancreatic ducts will be smaller that the other and may even disappear.Which one is destined to become smaller or absent depends on the species.

Avian...The avian digestive tract features:— a crop, which develops as a diverticulum of the esophagus;— a two-compartment stomach:

1] proventriculus (glandular stomach) and2] ventriculus or gizzard (stratified squamous epithelium and

heavy muscles for grinding);— a pair of ceca;— a cloaca which opens externally by means of a vent.

Pancreas & Liver Development

duodenumgall

bladder

hepaticdiverticulum

pancreas(right lobe)

pancreas(left lobe)

hepatic ducts

35

Mesenteries...

Mesenteries are formed by splanchnic mesoderm when the embryonic gut is created as theembryo assumes a tubular shape.

Splanchnic mesoderm is separated from somatic mesoderm by the embryonic coelom. Meso-derm lining the coelom transforms into serous membrane, making the coelom a serous cavity.

Caudal to the pharynx (head process),dorsal and ventral “mesenteries” of theesophagus persist as mediastinum in thethorax.

In the abdomen, a dorsal mesentery iscontinuous, but a ventral mesentery is absentcaudal to the stomach and cranial to thecloaca.

The dorsal mesentery becomes: greateromentum, mesoduodenum, mesentery(mesojejunum and mesoileum), mesocolon,and mesorectum.

The original dorsal mesogastriumelongates greatly as it forms greater omentum.The left lobe of the pancreas develops within the dorsal portion of the greater omentum. The spleen develops within thegreater omentum from blood vessels that accumulate in the vicinity of the greater curvature of the stomach.

As the midgut elongates and rotates around the cranial mesenteric artery, portions of themesojejunum and mesoileum come into contact near the dorsal body wall and fuse, forming the rootof the mesentery. Parts of the mesoduodenum and mesocolon also fuse to the root the mesentery.

The ventral mesentery, in which the liver develops, becomes the lesser omentum and coro-nary and falciform ligaments of the liver. Caudally, ventral mesentery becomes median ligament ofthe urinary bladder.

stomach

cecum cloaca

Mesenteries (lateral view)mesentery

lesseromentum

falciform ligament

spleen

liver

umbilicus

median ligam

ent o

f

the urinar

ybl

adde

r

dors

alm

esog

astri

um

(gre

ater

omen

tu

m)

ventral mesogastrium

mesocolon

Mesoderm = somite = intermediate = lateral

neural tubenotochord

foregut

mesentery

yolksac

embryoniccoelom

extra-embryoniccoelom

somatopleuresplanchnopleure

LateralBody Folds

36

Respiratory SystemThe respiratory system consists of the nasal cavity, pharynx, larynx, trachea and lungs. The

lining of the nasal cavity is derived from ectoderm; the lining of the rest of the respiratory systemcomes from endoderm.

Summary of Nasal Cavity Development:

• bilateral nasal (olfactory) placodes appear (the placodes are ectodermal thickenings at theventral tip of the frontonasal prominence)

• placodes become nasal pits by growth of medial and lateral nasal processes of thefrontonasal prominence

• continued outgrowth of nasal processes elongates the nasal pits and transforms them into anasal cavity

• right and left medial nasal processes fuse to form a primary palate (incisive bone & rostralupper lip) and a nasal septum (lateral nasal processes become nose cartilage and nasal & lacrimalbones)

• development ofa secondary palateestablishes three sepa-rated cavities (right &left nasal cavities and theoral cavity) and dividesthe pharynx into threecompartments (na-sopharynx, oropharynx,& laryngopharynx)

• conchae (scrollsof thin bone covered by mucosa) originate as cartilaginous ridges from bones of the nasal cavity wall

• paranasal sinuses (diverticula of the nasal cavity) developpostnatally.

Larynx, Trachea and Lungs:

These respiratory structures originate as an evagination ofendoderm along the floor of the pharynx. The evagination is designatedthe laryngotracheal groove.

From lateral walls of the laryngotracheal groove, ridges growmedially, and fuse along the midline, establishing a tracheoesophagealseptum. The septum separates a laryngotracheal tube (future trachea &lung buds) from the esophagus.

The larynx develops rostrally, where the lumen of the grooveretains communication with the pharynx.

Palate Formation

nasal septum

nasal pit

primary palate

secondarypatate

concha

tongueoral cavity

nasal cavity

Transverse ViewVentral View

nasal septum

secondarypatate

nasal cavity

Laryngo-TrachealGroove

(ventral view)

pharynx

L-T tube

L-T groove

CUT

37

Larynx:The larynx originates from bilateral laryngeal (arytenoid) swellings and a rostral epiglottal

swelling bordering the opening that persists between the laryngotracheal groove and the pharynx.Pharyngeal (branchial) arches IV-VI form laryngeal cartilages. Laryngeal muscles develop

from somitomeres that migrated to pharyngeal arches IV-VI. The larynx is innervated by the vagusnerve (the cranial nerve associated with arches IV-VI).

NOTE: The lumen of the larynx and trachea become plugged as a result of epithelial proliferation. Alumen is re-established by canalization. Selective canalization produces laryngeal ventricles,i.e., cavities lateral to the vocal folds that are necessary if the folds are to vibrate.

Trachea and bronchi:The laryngotracheal tube grows caudally into splanch-

nic mesoderm located ventral to the pharynx.The blind, caudal end of the tube develops a bi-lobed

lung bud which grows to form the future principal bronchi.Outgrowths of each principal bronchus form future

lobar bronchi, each of which gives rise to outgrowths thatbecome future segmental bronchi, each of which gives rise toadditional series of bronchial branchings. The bronchialbranchings continue to occur throughout the fetal period andinto the postnatal period.

Meanwhile, the trachea elongates so that bronchi areshifted caudally into the thorax.

NOTE: In ruminants and swine the laryngotracheal tube givesrise to a right tracheal bronchus in addition to right andleft principal bronchi.

left laryngeal swelling

I

I I

III

I Vbranchial(visceral)

archesI-IV

I

I I

III

I V

pharyngealpouches

I-IV

proximalepiglottal swelling

distaltongueswellings

Dorsal View of Floor of Pharynx (roof removed) Dorsal View of Larynx

epiglottis

piriformrecess

leftarytenoidcartilage

aryepiglottic fold

vocal fold

laryngeal opening

cricoidcartilagethyroid

cartilage

Bronchial Development(Dorsal View)

PorcineEarlyStage

Later Stage

principalbronchus

trachealbronchus

lobarbronchus

segmentalbronchus

trachea

38

Lungs:Continued branching of the bronchial tree produces additional bronchioles and terminal sacs

from which alveoli develop. Splanchnic mesoderm forms the cartilage, fascia, smooth muscle, andvessels of the lung.

Initially, bronchiole branches are solid cores of cells that must undergo canalization (thedeveloping lung has the histologic appearance of a gland). Eventually, terminal branches becomehollow, dilated, and sac-like with a thin epithelium (terminal sacs). Alveoli are created by the forma-tion of septae that partition the terminal sacs.

Breathing movements take place in utero to prepare for postnatal respiration. At birth, lungscontain amniotic fluid that drains or is absorbed as air is breathed. Alveolar cells produce a phospho-lipid surfactant that reduces surface tension and thus facilitates alveolar expansion (as opposed toalveolar collapse).

NOTE: Species differ in degree of maturity of the lung at birth. Also, within a singlelung, distal regions are less mature than proximal ones. Formation of new alveolioccurs post-natally to a considerable extent in all mammals. Subsequently, lunggrowth is due to hypertrophy (increased size) of alveoli and air passageways.

capillary

terminalsac

squamous epithelium

cuboidal epithelium

septum future alveolus

septum

future alveolus

terminalsac

Alveolar Formation

39

Urinary SystemIntermediate mesoderm

NOTE: Intermediate mesodermis situated between somites andlateral mesoderm (somatic andsplanchnic mesoderm borderingthe coelom). All mesoderm isderived from the primarymesenchyme that migratedthrough the primitive streak.

Intermediate mesoderm (plus adjacent mesothelium lining the coelom) forms a urogenitalridge that consists of a nephrogenic cord (which forms kidneys & ureter) and a gonadal ridge (forovary/testis & female/male genital tract formation). Intermediate mesoderm also gives rise to adrenalcortex.

NOTE: Urine production essentially requires an increased capillary surface area(glomerulus), epithelial tubules to collect plasma filtrate and extractdesirable constituents, and a duct system to convey urine away from the body.

Kidneys

Three kidneys de-velop from each nephrogeniccord. They develop chrono-logically in cranial-caudalsequence, and are designatedpro—, meso—, and meta—,respectively.

The pronephros and mesoneph-ros develop similarly: the nephrogenic cordundergoes segmentation, the segments becometubules, and the tubules drain into a duct. Eventu-ally the tubules disintegrate.

1] Pronephros—consists of (7-8) primitivetubules which fuse to form a pronephric duct thatgrows caudally and terminates in the cloaca. Thetubules soon degenerate, but the pronephric ductpersists as the mesonephric duct. (The pronephros isnot functional, except in sheep.)

Although kidneys may function in-utero, they arenot essential because the placenta is capable ofremoving toxic agents from fetal blood.

Nephrogenic Cord (left)

pronephros

mesonephros

metanephros

mesonephric duct

mesonephric tubules

cloaca

somite

intermediate mesoderm(becomes urogenital ridge)

lateral mesoderm:

somaticsplanchnic

notochord coelom

neuralgroove

ectoderm

endoderm

spinal ganglion

neuraltube

notochord

aorta

mesentery

gut

somite

bodywall

coelom

glomerulus mesonephricduct

mesonephrictubule

40

2] Mesonephros—consists of (70-80) tubules induced to form by the mesonephric duct(former pronephric duct). One end of each tubule surrounds a vascular proliferation (glomerulus)produced by a branch of dorsal aorta. The other end communicates with the mesonephric duct. Themesonephros eventually degenerates, except for a few caudal tubules and the mesonephric ductwhich become testicular channels and epididymis/ductus deferens in the male. (The functional develop-ment of the mesonephros is inversely related to the numbers of tissue layers in the placenta.)

3] Metanephros—becomes the adult kidney and ureter ofmammals, birds, and reptiles. The metanephros forms in the pelvicregion and, by differential growth, it “ascends” cranially into the abdo-men. It is lobulated initially and subsequently becomes smooth in manyspecies. The metanephros originates from two sources:

— a ureteric bud (induced by neural tube) grows out of the meso-nephric duct in the region of the cloaca; the bud eventually developsinto the ureter, renal pelvis, and numerous collecting ducts;

— metanephrogenic mass is the caudal region of the nephro-genic cord (when the ureteric bud grows into the mesoderm, it induces the mass todevelop; in turn, the mass induces the cranial end of the ureteric bud to differentiateinto renal pelvis and collecting tubules—these induce mass cells to form nephrons).The metanephrogenic mass forms nephrons in the following manner:

• adjacent to collecting tubules, mesodermal cells proliferate toform cell cords that canalize and elongate, becoming S-shaped, meta-nephric tubules and eventually nephrons;

• one end of each metanephric tubule establishes communicationwith a collecting tubule; the other end of the tubule expands and sur-rounds a capillary glomerulus (forming a glomerular capsule);

• between the two ends, each metanephric tubule differentiatesinto regions (proximal segment, thin loop, and distal segment) character-istic of a nephron

NOTE: Nephrons develop from deep to superficial in the kidney. Many of the early nephrons subse-quently degenerate as a normal occurrence. Nephrons continue to form and mature postnatally(except in the bovine); thereafter, nephrons cannot be replaced if they are damaged.

Metanephros

uretericbud

metanephrogenicmass

renal pelvis

urachus

urinarybladder

urethra rectum

ureter

ductusdeferens

cloaca

urorectal septum

allantois

Nephron Formation

collecting duct

collectingtubule

glomerulus

metanephrictubule

hollow cordmesenchyme

cell cord

collecting duct

futurenephron

41

Urinary Bladder and Urethra

The cloaca is divided by a urorectal septum into a rectumand a urogenital sinus. The septum also divides the cloacal mem-brane into an anal membrane and a urogenital membrane. Themembranes subsequently degenerate, resulting in an anus andurogenital orifice, respectively.

Cranially, the urogenital sinus opens into the urachus, theintra-embryonic stalk of the allantois. The urogenital sinus may be

divided into a pelvic (cranial) region and a phallic (caudal) region.

Urinary bladder develops from an expansion of the urachus and the cranial end of theurogenital sinus. The expansion incorporates the mesonephric duct (future ductus deferens) andureter into the dorsal wall (trigone region) of the future bladder. Differential growth of the dorsalwall results in the mesonephric duct and ureter having separate openings with the positions of theopenings switched cranio-caudally.

Urethra develops from urogenital sinus. The development is gender specific:In females, the mid region of the urogenital sinus becomes urethra. (The caudal region of the

urogenital sinus become vestibule and vagina arises as an outrowth of the future vestibule.)In males, the pelvic urethra develops from the mid region of the urogenital sinus and the

penile urethra develops from elongation of the caudal end of the urogenital sinus.

NOTE: In the fetus, urine is discharged into the allantoic cavity through theurachus and into the amniotic cavity through the urogenital orifice.

Abnormalities of development include:• Hydronephrosis (cystic/polycystic kidneys) results from ureteric atresia or from failure of

nephrons to communicate with collecting tubules.• Patent urachus (urachal fistula) results from a failure of the allantoic stalk to close at birth.

Also, vesicourachal diverticulum (urachus persisting as a blind pouch) is a source of chronic cystitis.• Ectopic ureter, where the ureter opens into the urethra or vagina instead of the bladder, is a

source of incontinence.

Adrenal CortexThe adrenal gland consists of an adrenal medulla and an adrenal cortex that are embryologically, histologically,

and functionally different, even though they are combined grossly. The adrenal medulla is derived from neural crest(ectoderm). The adrenal cortex arises from cells of mesonephric nephrons that dissociate from the nephron and migrateto the location of the adrenal medulla.

adrenalcortex

adrenalmedulla

Adrenal Gland

neural crestcells

cortex primordium

mesonephricduct ureteric bud

urorectalseptum

cloacalmembrane

allantois

urachus

urogenitalsinus

rectum

42

Genital SystemDevelopment of genitalia involves transition through an indifferent stage in which gonads,

genital ducts and external features appear the same in both sexes. Most genital anomalies involvesome combination of intersex development.

GonadsIndifferent stage. Each gonad arises from a gonadal ridge, a thickening of intermediate

mesoderm and overlaying coelomic mesothelium that develops ventromedial to the mesonephrickidney. The parenchyma of a gonad consists of germ cells and supporting cells:

— supporting cells are derived from invading coelomic mesothelial cells, augmented by cellsfrom disintegrating mesonephric tubules; the invading cells form cellular cords (gonadal cords) thatradiate into gonadal ridge mesoderm;

— primordial germ cells arise from yolk sac endoderm; they migrate to the gut and thenthrough dorsal mesentery to reach the gonadal ridge.

Germ cells proliferate and migrate into cellular cords to become surrounded by supportingcells (germ cells that fail to enter a cellular cord undergo degeneration).

Testis. The cellular cords containing germ cells hypertrophy into hollow tubules, calledseminiferous tubules. Germ cells within seminiferous tubules differentiate into spermatogonia. Deepcellular cords lacking germ cells become tubules of the rete testis (located centrally in the testis).The duct system is not completely canalized until puberty.

Supporting cells that form walls of the seminiferous tubules differentiate into sustentacular(Sertoli) cells. Mesenchymal testicular cells become two populations of interstitial cells—onepopulation produces androgens immediately, the other population delays androgen production untilsexual maturity. The androgens stimulate male genitalia development.

Coelomic mesothelium covering the testis becomes visceral peritoneum. Mesenchyme deepto the mesothelium proliferates and becomes tunica albuginea.

NOTE: In ovaries, 90% of the germ cells fail to become incorporated into follicles;they complete meiosis and degenerate. The onset of meiosis is delayed inembryos of species having longer gestations to reduce germ cell degeneration.

degeneratingmesonephric

duct & tubules

paramesonephricduct

IndifferntGonad

Ovary Testis

germ cell

mesonephric duct

germ cell

paramesonephric duct

mesothelial cords

mesonephric duct

follicle

seminiferous tubule

mesonephrictubule

rete testis &efferent ductules

migrating germ cells

43

Ovary. The cellular cords that contain germ cells undergo reorganization so that individualgerm cells become isolated, each surrounded by a sphere of supporting cells—forming primordialfollicles. Germ cell and follicle proliferation is completed before birth. Germ cells (oogonia) differ-entiate into primary oocytes that commence meiosis, but remain in prophase of Meiosis I untilovulation in the reproductively capable female.

Genital ducts, accessory glands, and ligaments

Indifferent stage. Both sexes have male (meso-nephric) and and female (pramesonephric) genital ductsand a urogenital sinus. The mesonephric (Wolffian) ductpersists after the mesopnephros disintegrates. Aparamesonephric (Mullerian) duct develops along the ventro-lateral surface of the mesonephros. It begins as a groove atthe coelomic surface. The edges of the groove merge toform a core of cells that canalize and elongate.

Which duct system develops, is determined bytesticular hormones. Male development requires testoster-one. The testis ( sustentacular cells) also releases an inhibitoryhormone that suppresses female duct development.

Female. In the absence of testosterone, mesonephric ducts fails to develop (histo-logic remnants may be found in the vicinity of thevestibule).

The cranial region of each paramesonephric ductremains open and forms the future uterine tube. Caudalto this, each duct becomes uterine horn. Further cau-dally, the bilateral paramesonephric ducts shift mediallyand fuse into a single tube that ends blindly in contactwith the urogenital sinus. The fused ducts becomeuterine body, uterine cervix, and the cranial third of thevagina.

NOTE: The degree of fusion of paramesonephric ducts is species dependent. Among domestic animalsfusion is greatest in the horse and least in carnivores. Rodents and the rabbit have a single vaginabut two cervices. Marsupials have a double vagina (no fusion at all).

The vagina has a dual origin. The cranialone-third comes from fused paramesonephricducts. The caudal two-thirds comes from thevaginal plate, a solid tubercle that growsoutward from the urogenital sinus at the site ofcontact between the urogenital sinus and thefused paramesonephric ducts. Degeneration ofthe center of the solid tubercle creates thevaginal lumen. A hymen may persist where thevagina joins urogenital sinus. The urogenitalsinus forms the vestibule.

FemaleGenital

Duct

ovary

uterus

degenerating mesonephros

broad ligament(urogenital fold)

Vaginal Development(lateral view)

urogenitalsinus vestibule

urethra

hymen

vaginal lumenvaginal

plate

lumen of fusedpramesonephric

ducts

cervix

uterinebody

Transverse Section throughUrogenital Ridge

gonadparamesonephric

duct coelomicmesothelium

mesonephrictubules

mesonephricduct

44

efferent ductulesrete testis

seminiferoustubule

tunicaalbuginea

epididymis

gubernaculum

ductusdeferens

degenerating paramesonephric

duct

Male Gonad& Ducts

(left side)

Male. Paramesonephric ducts regress(although remnants may be found in the adultmale). About a dozen mesonephric tubules areconverted to efferent ductules (they already communi-cate with the mesonephric duct but must establish communi-cation with the rete testis).

The cranial region of the mesonephric ductundergoes extensive elongation and coiling tobecome the epididymis; the remainder of the ductbecomes ductus deferens. The mesonephric ductempties into the urogenital sinus which becomesthe pelvic and penile urethra.

Glands. Prostate and bulbourethral glandsdevelop (in typical gland fashion) from evagina-tions of urogenital sinus epithelium (endoderm).Each vesicular gland (seminal vesicle) arises as anepithelial evagination from the caudal region of themesonephric duct (mesoderm). Surroundingmesenchyme becomes gland smooth muscle.

Ligaments. When the mesonephros degen-erates, it leaves behind a urogenital fold thatbecomes genital duct ligaments.

In females, the urogenital fold becomes:suspensory ligament of the ovary , mesovarium,mesosalpinx, and the cranial part of the mesometrium. The caudal part of the mesometrium is formedby a tissue “shelf” that accompanies each paramesonephric duct when it shifts medially to fuse withits counterpart. In males, the urogenital fold becomes mesorchium and mesoductus deferens.

A caudal extension of the urogenital fold that runs along the body wall and into the inguinalregion may be designated inguinal fold. It becomes the proper ligament of the ovary and roundligament of the uterus in females. In males, it gives rise to the gubernaculum of the fetus whichsubsequently in the adult becomes the proper ligament of the testis and ligament of the tail of theepididymis. These derivatives of the inguinal fold preclude closure of the body wall, thus are respon-sible for formation of the inguinal canal and vaginal process (evagination of the coelom).

Descent of the GonadIn both sexes, there is a caudal shift of the gonad from its original position. The shift is due to

elongation of the body and a variable degree of retention by the inguinal fold derivative that indi-rectly attaches to the gonad. In females, the ovary remains intra-abdominal and the extent of caudalshift is species dependent (e.g., slight in the bitch vs. to the pelvis in the cow)

Testicular descent. The gubernaculum orignates as a condensation of the mesenchymewithin each inguinal fold. Under the influence of gonadotropins and testicular androgens, the guber-naculum accumulates fluid and become a gel mass as large in diameter as a testis. The swollengubernaculum enlarges the inguinal canal. Subsequent outgrowth of the scrotal wall and dehydrationof the gubernaculum passively pulls the testis to the inguinal canal, where a sudden increase in intra-abdominal pressure can pop it through the canal into the scrotum.

45

Human External Genitalia Development

Female MaleIndifferent

Stage

genital tubercle

urogenital fold

genital swelling

clitoris

labium major

labium minorvagina

hymen

urethralopening

vestibule

urethral openingglans

prepuce

penis(phallus)

scrotum

anus

urogenital sinus

anus

External Genitalia

Indifferent stage. External genitalia are derived from three different swellings in the in-guinal region:

• a genital tubercle, located at the ventral commissure of urogenital folds;• bilateral urogenital folds that border the urogenital orifice, the folds elongate as the orifice

elongates ventrally (Urogenital folds are formed when the urorectal septum divides the cloaca. Cloacal folds become

urogenital folds and anal folds surrounding the respective orifices.)

• bilateral genital (labioscrotal) swellings are lateral to the urogenital swellings (in domesticmammals these develop only in males, unlike humans where the swellings develop in both sexes andform major labia in women).

Female. The urogenital orifice becomes vulval cleft, which opens into the vestibule (urogeni-tal sinus). The genital tubercle becomes the clitoris (generally not well developed in domestic ani-mals). The urogenital folds enlarge, overgrow the genital tubercle, and become labia of the vulva.Genital swellings disappear in female domestic animals.

Male. Growth at the base of the genital tubercle forms an elongate phallus. The originaltubercle becomes glans at the tip of the phallus. The urogenital orifice (sinus) elongates with thephallus forming a urogenital groove. The penile urethra is created when the groove closes by medialmerger of urogenital folds in proximal to distal sequence.

The opening of the distal end of the penile urethra, within the original genital tubercle, isformed by ectoderm invasion and canalization which establishes communication between the exte-rior and the endodermal penile urethra. Adjacent mesenchyme forms erectile tissue, tunica albug-inea, muscle, and bone (carnivores).

The prepuce is formed by a ring of ectoderm that invades into the mesenchyme of the freeend of the phallus, dividing tissue into a penis encircled by preputial skin. (Except in the cat, thephallus of domestic mammals elongates deep to the skin of the ventral body wall.)

Genital swellings enlarge and merge at the midline to form a scrotum. The scrotum initiallyoverlies the gubernaculum and vaginal process in the inguinal region, but then shift cranially (exceptin the cat and pig).

46

Mammary Glands

In both sexes, a mammary ridge of thickened ectoderm forms bilaterally from the axillary tothe inguinal region. Mammary buds develop periodically along the ridge. From each bud, cell cordsinvade underlaying mesoderm to form a mammary gland composed of one to a dozen (speciesdependent) lactiferous duct systems. Following canalization, lactiferous ducts open into a pit (in-verted nipple) that becomes a nipple following proliferation of underlaying mesoderm.

The number of mammary glands and their location is species dependent. Commonly, extrabuds buds develop and degenerate, failure to degenerate results in supernumerary teats.

Dog(ventral view)

mammaryridge

mammarybud

47

Face, Nasal Cavity, Mouth, &PharynxFace:

The face develops from outward growth of tissue located rostral to the pharynx. The lowerjaw and most of the upper jaw are formed by out growths of the first pharyngeal (branchial) arch.Theupper incisor region and the nose and forehead (frontal region) are formed from tissue locatedrostral to the neural tube (frontonasal prominence). The development process proceeds as follows:

— the first pharyngeal (branchial) arch grows outward as two processes:• a lower (mandibular) process grows first and forms the mandible and soft tissue

of the lower jaw (right and left processes fuse to form the mandibular symphysis)

• an upper (maxillary) process grows to form most of the upper jaw (caudalto the incisor teeth)

— dorsal to each maxillary process, a frontonasal prominence expands outward;it soon becomes divisible into a frontal prominence (which forms frontalbone of the forehead) and medial & lateral nasal processes.

nasal placode maxillaryprocess

mandibularbranchial arch (I)

hyoidbranchialarch (II)

medial nasalprocess lateral

nasalprocess

eye

nasal pit

mandibularprocess

stomodeum

frontonasal prominence

maxillaryprocess

nasolacrimalgroove

eyenostrilupper

jaw

lowerjaw

mouth

hyoidapparatus

nasal placode

oropharyngealmembrane(deep wall of stomodeum)

pharynx

Head Process(Ventral View)

SagittalSection

LateralSurface

View

early

late

branchialarches

nasalpit

Three-week old embryo

frontalprominence

48

• Six pairs of pharyngeal (branchial) arches develop, although only the first three are superficiallydistinct in mammals. Adjacent pharyngeal arches are separated by pharyngeal clefts (grooves). Theexternal clefts are apposed internally by pharyngeal pouches.

• All mesenchyme within pharyngeal arches and within the frontonasal prominence isectomesenchyme, derived from neural crest. Ectomesenchyme forms bone and fascia of the faceand cranium, since these develop from pharyngeal arches. (Only bones of the base of the skulldevelop from mesodermal mesenchyme, from occipital somites.)

• Skeletal muscle of the head is derived from either somites or somitomeres that migrate into pharyn-geal arches or the frontonasal prominence. Each arch is innervated by a cranial nerve that willsupply structures derived from the arch.Note: Somitomeres resemble somites, but they originate from paraxial mesoderm located

rostral to the notochord. There are seven pair of somitomeres. They give rise toextraocular, masticatory, facial, and some pharyngeal muscles.

Nasal cavity:Initially, a nasal placode (ectoderm thickening) appears bilaterally at the rostral end of the

frontonasal prominence. Subsequent growth of surrounding medial and lateral nasal processesforms a nasal pit (bilaterally). Continued growth and elongationof each nasal pit results in a primitive nasal cavity.

The bilateral rostral openings of the nasal cavity be-comes external nares (nostrils) and ectomesenchyme surround-ing them forms cartilage of the nose. Each lateral nasal process give

rise to alar cartilage of the nose, nasal bone and lacrimal bone. A nasolacri-mal duct is formed by ectoderm along the seam where the lateral nasalprocess meets the maxillary process.

Fusion of right and left medial nasal processes forms aprimary palate rostrally and the nasal septum caudally. Theincisive bone, including upper incisor teeth and the rostral upperlip, constitutes the primary palate. The nasal septum consists ofbone, cartilage, and a patch of soft tissue membrane that sepa-rates right & left halves of the nasal cavity. The vomer bone forms

the ventral border of the nasal septum caudal to the nose.

Nasal and oral cavities are initially separated by an oronasal membrane which subsequentlydegenerates allowing the cavities to communicate with one another. In mammals, formation of asecondary palate shifts the nasal-oral communication caudally into the pharynx.

Nasal Processes:

medial

lateral

eye

nasal pit

maxillary processmandibular process

nasalpit

stomadealcavity

oronasal membrane

fusedmedial nasalprocesses

lateralnasal

process

mandibularprocess

maxillaryprocess

nasalcavity

nasalseptum

oralcavity

palatineprocess

secondarypalate

tonguetongue

mandible

nasalbone

maxilla

nasalcavity

oralcavity

49

Palate: Two palates are formed. The primary palate, which becomes incisive bone, is formed by

medial nasal processes. The secondary palate is formed by bilateral medial extensions of maxillaryprocesses. The exten-sions (palatine processes)meet at the midline,merging dorsally withnasal septum and ros-trally with primarypalate. The secondarypalate (hard palate)separates nasal and oralcavities. Caudal exten-sion of the secondarypalate into the pharynx,forms a soft palate which divides the rostral pharynx into dorsal (nasopharynx) and ventral (orophar-ynx) chambers.

• Cleft palate results from failure of the palate to close along the midline, leaving a gapor cleft. The secondary palate is affected more commonly than the primary palate.The condition may be inherited or be the result of exposure to a teratogen (anagent that causes birth defects). Cleft palate is often fatal in animals due to inabil-ity to suckle or because of aspiration of milk into the lungs (aspiration pneumo-nia).

• Failure of medial nasal processes to fuse (primary cleft palate), produces hare lip(cheiloschisis) and related defects. (Hare lip alone is normal is hares, sheep, etc.).

Conchae: Conchae (turbinates) are scrolls of thin bone covered by mucosa that grow intoeach nasal cavity. Conchae originate as cartilaginous ridges of bones of the wall of the nasal cavity.

Paranasal sinuses: Sinuses arise as epithelial lined diverticula of the lining of the nasalcavity. The extent of sinus development varies with species, most of the development occurs postna-tally. Newborn animals have cute, rounded heads that become angular with age as sinuses develop.

Vomeronasal organ: This is a specialized olfactory sense organ located rostrally in the floorof each nasal cavity. The organ is produced by an outgrowth of nasal epithelium that forms a cau-dally-closed tube.

Mouth:The mouth (oral cavity) develops as a consequence of the formation of upper and lower jaws.

The first evidence of a mouth is the stomodeum, a rostral depression surrounded by prominences.Outgrowth of the prominences produces a stomodeal cavity.

The deep wall of the stomodeum (oropharyngeal membrane) is composed of a layer ofsurface ectoderm apposed to a layer of endoderm (rostral wall of the pharynx). The oropharyngealmembrane soon becomes fenestrated and disappears (the palatoglossal fold marks its location in the adult).

Initially, stomodeal cavity and nasal pits are separated by an oronasal membrane. Subse-quently, the oronasal membrane degenerates and oral and nasal cavities communicate freely. Eventu-ally a secondary palate develops, shifting oral-nasal communication caudally into the pharynx.

Palate Formation

nasal septum

nasal pit

primary palate

secondarypatate

concha

tongueoral cavity

nasal cavity

Transverse ViewVentral View

nasal septum

secondarypatate

nasal cavity

50

Lips and gingivae:In the ectoderm lining the stomodeal cavity, an

arc of thickened ectoderm, the labiogingival lamina,forms along upper and lower jaws. The lamina invagi-nates into underlying ectomesenchyme, forming a labiog-ingival groove. The groove forms the future vestibule.Tissue external to the groove forms the future lips, andtissue medial to the groove forms gingivae. Fusion ofupper and lower lips caudally forms cheeks.

Teeth:An arc of periodically thickened ectoderm, situ-

ated inside of the labiogingival lamina, constitutes thedental lamina. Invaginations of laminar cells form dentalbuds. If a bud is to form a deciduous tooth, an additionalbud for its permanent replacement develops superficialand medial to the deciduous dental bud. Each bud devel-ops into a tooth in the following way:

— the bud assumes a cup-shaped configurationbecoming an enamel organ; condensation ofectomesenchyme within the concavity of the cup forms adental papilla;

— the inner epithelial layer of the enamel organinduces ectomesenchyme of the dental papilla to form anepithelial layer of odontoblasts that deposit the dentin ofthe tooth;

— the odontoblasts induce the inner epithelium ofthe enamel organ to differentiate into ameloblasts thatform enamel of the crown of the tooth;

— ectomesenchyme surrounding the enamelorgan condenses intoa dental sac thatgives rise to threelayers:

1] Outer cells of thedental sac differenti-ate into osteoblaststhat deposit bone ofthe alveolus (socket receiving the tooth).

2] Middle layer of the dental sac forms periodontal ligament(which anchors the tooth within the alveolus).

3] Inner cells of the sac become cementoblasts that producecementum (modified bone) which adheres to the surface of thetooth, particularly the dentin surface of the root of the tooth.

Note: Eventually, osteoclasts re-absorb encasing superficialbone in preparation for tooth eruption.

enamel

dentin

pulp cavity

cementum

CROWN

ROOT

labiogingival laminadental lamina

LATERAL MEDIAL

labigingivalgroove

dentalbud

enamelorgan

permanenttooth bud

ameloblast layer

bone

enamel

dentin

odontoblast layer toothpulp

vestibule

gingiva

dentalpapilla

lip

TRANSVERSEVIEW

oral cavity(surface view)

51

Tongue:The tongue develops from four swellings situated on the floor of the pharynx:— the body/apex of the tongue is formed by paired distal (lateral) swellings that fuse along

the midline and grow forward into the oral cavity, thereby acquiring an ectodermal coat. The body ofthe tongue arises predominantly from the first pharyngeal arch. General sensation is from the trigeminal

nerve (V). The second pharyngeal arch also contributes. Taste sensation is from the facial nerve (VII).

— the root of the tongue is formed by the proximal swelling and covered by endoderm. Itarises from the third pharyngeal arch. Sensation is supplied by the glossopharyngeal nerve (IX) .

— the median swelling contributes significantly to the tongue only in ungulates (especially in

cattle where it forms a prominent bulge);— muscles of the tongue originate from occipital somites (innervated by hypoglossal nerve (XII)).

Salivary glands:Salivary glands are derived from ectoderm (parotid, zygomatic, and labial and buccal accessory

salivary glands) or endoderm (mandibular and mono- and poly-stomatic sublingual salivary glands).

The process of salivary gland formation is typical of exocrine gland development in general:— localized proliferation of surface epithelial cells forms a cellular cord that invades the

underlying ectomesenchyme; the initial site of proliferation ultimately becomes the duct opening tothe surface;

— the invading cord of cells begins to branch, ultimately becoming the main duct andbranched ducts of the gland;

— masses of epithelial cells accumulate at the ends of each branch, ultimately formingsecretory acini of the gland;

— the epithelial cords and masses canalize (become hollow) and the gland becomes func-tional; growth of the jaw causes elongation of the main duct.

NOTE: A polystomatic gland is one that has many duct openings to the surface. Such glands arise as aseries of independent epithelial cords. Although they are independent glands, they appear toform a single mass and in gross anatomy they are collectively identified as a single gland.

I

II

III

IVpharyngeal(branchial)

archesI-IV

I

II

III

IV

pharyngealpouches

I-IV

proximalmedian

distaltongueswellings

Dorsal View of Floor of Pharynx (roof removed)

body of tongue

rootof

tongue

larynx

Canine Tongue(dorsal view)

52

Adenohypophysis:

The adenohypophysis developsfrom an ectodermal thickening(placode) in the roof of the sto-modeal cavity. The placodeevaginates to form an hypophysealpouch (Rathke’s pouch). Thepouch separates from the surfaceectoderm and wraps around theneurohypophysis, an outgrowth ofthe hypothalamus (brain). Depend-ing on species, the cavity of the pouchmay persist as a cleft separating a parstuberalis from a more voluminous parsdistalis of the adenohypophysis.

NOTE:The hypophysis (pituitary gland) consistsof a neurohypophysis and an adenohypo-physis. Both components are controlledby the hypothalamus of the brain. Theneurohypophysis is connected to thehypothalamus by means of an infundibu-lum. Axons of hypothalamic neurons runthrough the infundibulum and terminatein the neurohypophysis. Hypothalamicneurons must release hormones into theblood stream to control the adenohypo-physis.

Pharyngeal pouch derivatives:

A series of lateral evaginations of pharyngeal endoderm constitute pharyngeal pouches. There

are five pairs of pouches but in mammals the fifth pair is rudimentary, appearing as buds of the fourth.

The endoderm of each pharyngeal pouch is apposed to the ectoderm of a correspondingpharyngeal cleft. Pharyngeal clefts separate adjacent pharyngeal arches. In fish, the apposed endoderm-ectoderm degenerates forming a branchial cleft that becomes a gill slit (in mammals only one branchial cleft developsand it is transitory). [branchia (Gr.) = gills]

Pharyngeal pouches develop into various structures:

1st pouch —— tympanic (middle ear) cavity and auditory tube

2nd pouch —— fossa for the palatine tonsil and the fold covering it

3rd pouch —— external parathyroid gland and thymus

4th pouch —— internal parathyroid gland

5th pouch —— parafollicular cells of thyroid gland (avian ultimobranchial body)

epithelium

mesenchyme

epithelial cordbranch

acinarcell mass

main duct

epithelial cord

branchacinus

brain(third ventricle)

oral(stomadeal)

cavity

neurohypophysealbud

infundibulum

neurohypophysis

adenohypophysis

hypophyseal(Rathke's)

pouch

thirdventricle

Salivary GlandFormation

53

oral cavity

auditorytube &tympaniccavi ty

fossa ofpalatinetonsil

thymus &parathyroid(ext . )

parathyroid (int.) & part of thyroid

thyroid gland

1

2

3

4 & 5

Pharyngeal Pouch Derivatives(ventral view)

esophagus

The thyroid gland develops from endoderm of the floor of the pharynx. Initially there is formed athyroid diverticulum connected to the pharynx by a thyroglossal duct. (The duct degenerates since thethyroid is an endocrine gland, but rarely a remnant of the duct persists as a cyst that can enlarge andinterfere with breathing by compressing the pharynx). Depending on the species, the thyroid may remainsingle (pig) or split into bilateral lobes connected by an isthmus (horse) or become paired (dog).

Thyroid hormones have multiple metabolic effects. Parafollicular cells of the thyroid gland decrease blood Ca++

while parathyroid gland hormones increases blood Ca++.

The thyroid and parathyroids are endocrine glands and thus they lack ducts to an epithelialsurface.

I

II

III

IVPharyngeal

ArchesI-IV

I

II

III

IV

PharyngealPouches

I-IV

Floor of Pharynx (roof removed)

54

Lecture #3. Development of the Nervous Systemand Special Senses

NeurulationThe notochord induces overlaying ectoderm to become neuroectoderm and form a neural

tube. The following stages of neural tube formation are evident:• neural plate—ectodermal cells overlaying the notochord become tall columnar, producing

a thickened plate relative to the ectoderm that will produce skin.• neural groove—along the length of the neural plate, a central depression and bilaterally

elevated “shoulders” produces a neural groove.• neural tube—the dorsal margins of the neural groove merge medially, forming a neural

tube composed of columnar neuroepithelial cells surrounding a neural cavity. In the process ofseparating from overlaying ectoderm, some neural plate cells become detached from the tube andcollect bilateral to it, forming neural crest.

Note: The neural tube becomes the central nervous system (CNS), whichconsists of the brain and spinal cord. The cavity of the tube becomes theventricular system of the brain and the central canal of the spinal cord. Neural crest cells become neurons of the peripheral nervous system(PNS) that have their cell bodies located in ganglia, and neurolemmocytes(Schwann cells) of the PNS. Additionally, neural crest cells becomeadrenal medulla cells, melanocytes of skin and a variety of structures inthe face.

neural plate

ectoderm

notochordneuralgroove

neuralcrest

neuroepithelium

neural cavitymantlelayer

merginallayer

neuralcrest

12

3

4

5

55

Central Nervous System

Formation of neurons and glial cells from neuroepithelium:Neuroepithelium gives rise to neurons, glial cells (astrocytes

and oligodendrocytes), and ependymal cells (additionally, the CNS contains

blood vessels and microglial cells derived from mesoderm).Neuroepithelial cells have processes which contact the inner

and outer surfaces of the neural tube; they undergo mitotic divisionin the following manner:

— the nucleus (and perikaryon) moves away from the neural cavity forinterphase (DNA synthesis);

— the nucleus moves toward the neural cavity and the cell becomesspherical and looses its connection to the outer surface of the neural tube formitosis; this inward-outward nuclear movement is repeated at each cell division;

Some cell divisions are differential, producing neuroblastswhich give rise to neurons or glioblasts (spongioblasts) which giverise to glial cells (oligodendrogliocytes and astrocytes). Neuroblasts andglioblasts lose contact with surfaces of the neural tube and migratetoward the center of the wall of the tube;

Layers and plates of the neural tube:Cells that remain lining the neural cavity are designated

ependymal cells; they form the ependymal layer. Accumulatedneuroblasts and glioblasts form the mantle layer, a zone of high celldensity surrounding the ependymal layer. Surrounding the mantlelayer, a cell-sparse zone where axons of neurons and some glial cellsare present is designated the marginal layer. The mantle layerbecomes gray matter and the marginal layer becomes white matter of the CNS.

The lateral wall of the neural tube is divided intotwo regions (plates). A bilateral indentation evident in theneural cavity (the sulcus limitans) serves as a landmark todivide each lateral wall into an alar plate (dorsal) and abasal plate (ventral). Midline regions dorsal and ventralto the neural cavity constitute, respectively, the roof plateand the floor plate.

The basal plate contains efferent neuronsthat send axons into the PNS; the alar plate con-tains neurons that receive input from the PNS.

Neural Tube

neuroepithelium

neural cavity

mitosis

interphase

lum

en s

ide

ou

tsid

e w

all

wall

neuroepithelium neural cavity

marginal layer

mantle layerependymal layer

central canal

white matter

gray matter

Neural Tube Embryonic Spinal Cord

Embryonic Cord Regions

roof plate

alar plate

basal platefloor plate

sulcuslimitans

56

Embryonic Derived Definitive Associated Brain Division Brain Structures Brain Cavities Cranial Nerves

FOREBRAIN Telencephalon Cerebrum Lateral ventricles Olfactory (I)

Diencephalon Thalamus; Third Ventricle Optic (II)hypothalamus; etc.

MIDBRAIN Mesencephalon Midbrain Mesencephalic aqueduct III & IV

HINDBRAIN Metencephalon Pons and Cerebellum V

Fourth ventricle Myelencephalon Medulla Oblongata VI—XII

Neurons are incapable of cell division (except for neurons in olfactory epithe-lium). The last division of a neuroblast produces two neurons that are able to migratebut cannot divide. Neurons that fail to make viable contacts degenerate.

Note: A typical neuron has a cell body (perikaryon) and numerous processes emanating from thecell body. One process, the axon, is generally long and often encased in a myelin sheath formed byglial cells. Unstained myelin has a white “color”.

White matter refers to CNS regions that have a high density of myelinated axons. Gray matterhas sparse myelinated axons and generally a high density of neuron cell bodies.

Formation of the CNSThe cranial end of the

neural tube forms three vesicles(enlargements) that furtherdivide into the five primarydivisions of the brain. Caudal tothe brain the neural tube devel-ops into spinal cord.

Flexures: During develop-ment, the brain undergoes threeflexures which generally disappear(straighten out) in domestic animals.

The midbrain flexure occurs atthe level of the midbrain.

The cervical flexure appears atthe junction between the brain andspinal cord (it persists slightly indomestic animals).

The pontine flexure is concavedorsally (the other flexures are concaveventrally).

forebrain

Brain VesiclesBrain Divisions

midbrain

hindbrain

spinal cord

telencephalon(cerebrum)

diencephalon

optic cup

mesencephalon(midbrain)

metencephalon

myelencephalon(medulla oblongata)

spinal cord

Note: The portion of brain remaining after the cerebrum and cerebellum are removed is referred to as the brain stem.

57

pia mater

Medulla Oblongata

choroid plexus

mantle layer

marginal layer

ependymalcell layer

alar plate

basal plate

Spinal cord development— the neural cavity becomes central canal lined

by ependymal cells;— growth of alar and basal plates, but not roof

and floor plates, results in symmetrical right and lefthalves separated by a ventral median fissure and a dorsalmedian fissure (or septum);

— the mantle layer develops into gray matter, i.e., dorsal and ventral gray columns separated byintermediate gray matter (in profile, the columns are usually called horns); cell migration from the basal plate produces alateral gray column (horn) at thoracic and cranial lumbar levels of the spinal cord (sympathetic preganglionic neurons);

— the marginal layer becomes white matter (which is subdivided bilaterally into a dorsal funiculus

(bundle), a lateral funiculus, and a ventral funiculus ).

Greater degeneration of neurons within segments that do not innervate limbsresults in cervical and lumbosacral enlargements, i.e., enlargements of the spinal cordsegments that do innervate limbs.

Hindbrain: Medulla oblongata and pons:— alar plates move laterally, the cavity of the neural tube expands dorsally forming a fourth

ventricle; the roof of the fourth ventricle (roof plate) isstretched and reduced to a layer of ependymal cells covered bypia mater; a choroid plexus develops bilaterally in the roof of

the ventricle and secretes cerebrospinal fluid;

— the basal plate (containing efferent neu-rons of cranial nerves) is positioned medial to thealar plate and ventral to the fourth ventricle;

— white and gray matter (marginal & mantlelayers) become intermixed (unlike spinal cord) andcerebellar development adds extra structures.

Hindbrain: Cerebellum

NOTE: The adult cerebellum features surface gray matter, called cerebellar cortex. Cerebellarwhite matter is deep to the cortex, and three pair of cerebellar nuclei are located deep withinthe white matter. The cerebellum connects to the brain stem by means of three pair of cerebel-lar peduncles, each composed of white matter fibers. The cerebellar cortex is composed of three layers: a superficial molecular layer which isrelatively acellular; a middle piriform (Purkinje) cell layer consisting of a row of large cellbodies; and a deep granular (granule cell) layer composed of numerous very small neurons. The cerebellum functions to adjust muscle tone and coordinate posture and movement sothey are smooth and fluid vs. jerky and disunited.

— bilateral rhombic lips are the first evidence of cerebellar development; the lips are expan-sions of the alar plate into the roof plate; the rhombic lips merge medially, forming a midline isth-mus (the lips form the two cerebellar hemispheres and the isthmus forms the vermis of the cerebellum);

ependymal layer

central canal

white matter

gray matter

Embryonic Spinal Cord

58

Brain Divisions & Flexuresmedulla oblongata

diencephalonpons

midbrain cerebrum

cerebellum

neurohypophysis

midbrainflexure

cervicalflexure

— cellular migrations:• superficial and deep layers of neurons are

evident within the mantle layer of the future cerebellum;the deep cells migrate (pass the superficial cells) towardthe cerebellar surface and become Purkinje cells of thecerebrellar cortex; meanwhile, neurons of the superficiallayer migrate deeply and become cerebellar nuclei;

• neuroblasts located laterally in the rhom-bic lip migrate along the outer surface of the cerebellum,forming an external germinal layer (which continues toundergo mitosis); subsequently, neurons migrate deep tothe Purkinje cells and form the granule cell layer of the cerebellar cortex;

• some alar plate neurons migrate to the ventral surface of the pons, forming pontine nuclei which sendaxons to the cerebellum.

Migration of neuron populations past one another allows connections to be estab-lished between neurons of the respective populations. Neurons that fail to connect aredestined to degenerate. Connections are made by axons that subsequently elongate asthe neurons migrate and as overall growth occurs.

Midbrain— the neural cavity of the midbrain becomes mesencephalic aqueduct (which is not a ventricle

because it is completely surrounded by brain tissue and thus it lacks a choroid plexus).

— alar plates form two pairs of dorsal bulges which be-come rostral and caudal colliculi (associated with visual and auditoryreflexes, respectively);

— the basal plate gives rise to oculomotor (III) and tro-chlear (IV) nerves which innervate muscles that move the eyes.NOTE: The midbrain is the rostral extent of the basal plate (effer-ent neurons).

Forebrain (derived entirely from alar plate)

Diencephalon:— the neural cavity expands

dorsoventrally and becomes thenarrow third ventricle, the roof plate isstretched and choroid plexuses developbilaterally in the roof of the third ventricleand secrete cerebrospinal fluid;

— the floor of the thirdventricle gives rise to theneurohypohysis (neural lobe ofpituitary gland);

Developing Forebrain (transverse section)

future choroid plexus

lateralventricle

lateralventricle third

ventricle

mantle layer cerebral cortex

basalnucleus

diencephalontelencphalon (cerebrum)

colliculus

mesencephalaqueduct

III nerveMidbrain

59

— the mantle layer of the diencephalon gives rise to thalamus, hypothalamus, etc.; the thala-

mus enlarges to the point where right and left sides meet at the midline and obliterate the center of the third ventricle.

— the optic nerve develops from an outgrowth of the wall of the diencephalon.

Telencephalon (cerebrum):

— bilateral hollow outgrowths become right and left cerebral hemispheres; the cavity ofeach outgrowth forms a lateral ventricle that communicates with the third ventricle via an interven-tricular foramen (in the wall of each lateral ventricle, a choroid plexus develops that is continuous with a choroid

plexus of the third ventricle via an interventricular foramen);— at the midline, the rostral end of the telencephalon forms the rostral wall of the third

ventricle (the wall is designated lamina terminalis);— the mantle layer surrounding the lateral ventricle in each hemisphere gives rise to basal

nuclei and cerebral cortex;— cellular migrations that form cerebral cortex:

• from the mantle layer, cells migrate radially to the surface of the cerebral hemi-sphere, guided by glial cells that extend from the ventricular surface to the outer surface of thecerebral wall (thus each locus of mantle gives rise to a specific area of cerebral cortex);

• migration occurs in waves; the first wave (which becomes the deepest layer ofcortex) migrates to the surface of the cortex; the second wave (which forms the next deepest layer ofcortex) migrates to the cortical surface, passing through first wave neurons which are displaced to adeeper position; the third wave . . . etc. (the cerebral cortex has six layers.

Cell connections are established within the cerebral cortex as waves of newlyarriving neurons migrate through populations of neurons that arrived earlier.

NOTE: Carnivores are born with a nervous system that does not mature until about six weekspostnatally (mature behavior is correspondingly delayed). In herbivores, the nervoussystem is close to being mature at birth.

Forebrain (dorsal view)

laminal terminalis

Telencephalon (cross section)surrounding diencephalon

cerebral hemisphere

interventricularforamen

lateralventricle

diencephalon

cerebralcortex

lateralventricle

basalnucleus

basalnucleus

thirdventricle optic cup

thirdventricle

60

Peripheral Nervous System

NOTE: The peripheral nervous system (PNS) consists of cranial and spinal nerves. Nervefibers within peripheral nerves may be classified as afferent (sensory) or efferent (motor)and as somatic (innervating skin and skeletal muscle) or visceral (innervating vessels andviscera). The visceral efferent (autonomic) pathway involves two neurons: 1] a pregan-glionic neuron that originates in the CNS and 2] a postganglionic neuron located entirelyin the PNS. The glial cell of the PNS is the neurolemmocyte (Schwann cell). All afferent neurons have their cell bodies in sensory ganglia: spinal ganglia on dorsalroots or ganglia associated with cranial nerves. Somatic efferent and preganglionicvisceral efferent neurons have their cell bodies located in the CNS, but their axons extendinto the PNS. Postganglionic visceral efferent neurons have cell bodies in autonomicganglia.

— neurolemmocytes (Schwann cells) arise from neural crest and migrate throughout thePNS, ensheathing and myelinating axons and forming satellite cells in ganglia;

— afferent neurons originatefrom neural crest as bipolar cells thatsubsequently become unipolar; in thecase of cranial nerves, afferent neuronsalso originate from placodes (placode =

localized thickening of ectoderm in the head);

— postganglionic visceralefferent neurons arise from neural crest,the cells migrate to form autonomicganglia at positions within the head, orbeside vertebrae (along sympathetictrunk), or near the aorta, or in the gutwall (the latter are parasympathetic and come

from sacral and hindbrain regions);

— somatic efferent neurons andpreganglionic visceral efferent neuronsarise from the basal plate of the neuraltube; their cell bodies remain in theCNS and their axons join peripheralnerves;

Peripheral nerves establish contact early with the nearest somite, somitomere,placode, or branchial arch and innervate derivatives of these embryonic structures.

Innervation continuity is retained even when the derivatives are considerably displaced orwhen other structures have obstructed the pathway. The early establishment of an innervationconnection explains why some nerves travel extended distances and make detours to reach distantinaccessible targets. The foremost example is the recurrent laryngeal nerve which courses from the brainstem to thelarynx via the thorax, because the heart migrates from the neck to the thorax pulling the nerve with it.

Developing Peripheral Nervous System

neural tube

spinal ganglion

ventral root

notochord

aorta

dorsalmesentery

gut

lemmocytes(around axons)

autonomicganglion

adrenalmedulla

melanocytes

autonomicganglion

entericautonomicganglion

61

Note: Cranial nerves innervate specific branchial arches and their derivatives:trigeminal (V) - first branchial arch (muscles of mastication)facial (VII) - second branchial arch (muscles of facial expression)glossopharyngeal (IX) - third branchial arch (pharyngeal muscles)vagus (X) - 4 & 6 branchial arches (muscles of pharynx, larynx, & esophagus)

Formation of Meninges

Meninges surround the CNS and the roots of spinal and cranial nerves. Three meningeallayers (dura mater, arachnoid, and pia mater) are formed as follows:

— mesenchyme surrounding the neural tube aggregates into two layers;— the outer layer forms dura mater;— cavities develop and coalesce within the inner layer, dividing it into arachnoid and pia

mater; the cavity becomes the subarachnoid space which contains cerebrospinal fluid.

62

Special Senses

Formation of the EyeBoth eyes are derived from a single field of the neural plate. The single field separates into

bilateral fields associated with the diencephalon. The following events produce each eye:— a lateral diverticulum from the diencephalon forms an optic vesicle attached to the dien-

cephalon by an optic stalk;— a lens placode develops in the surface ectoderm where it is contacted by the optic vesicle;

the lens placode induces the optic vesicle to invaginate and form an optic cup while the placodeinvaginates to form a lens vesicle that invades the concavity of the optic cup;

— an optic fissure is formed by invagination of the ventral surface of the optic cup and opticstalk, and a hyaloid artery invades the fissure to reach the lens vesicle;

NOTE: The optic cup forms the retina and contributes to formation of theciliary body and iris. The outer wall of the cup forms the outer pigmentedlayer of the retina, and the inner wall forms neural layers of the retina. • The optic stalk becomes the optic nerve as it fills with axons travelingfrom the retina to the brain. • The lens vesicle develops into the lens, consisting of layers of lensfibers enclosed within an elastic capsule. • The vitreous compartment develops from the concavity of the opticcup, and the vitreous body is formed from ectomesenchyme that enters thecompartment through the optic fissure.

opticcup

lensvesicle

opticstalk

centralvessels

(in primates)

hyaloid arteryin optic fissure

Optic Stalk Optic Nerve

axons from the retinaoptic nerve fibers

63

— ectomesenchyme (from neural crest) surrounding the optic cup condenses to form innerand outer layers, the future choroid and sclera, respectively;

— the ciliary body is formed by thickening of choroid ectomesenchyme plus two layers ofepithelium derived from the underlying optic cup; the ectomesenchyme forms ciliary muscle and the collag-

enous zonular fibers that connect the ciliary body to the lens;— the iris is formed by

choroid ectomesenchyme plus thesuperficial edge of the optic cup; theouter layer of the cup forms dilatorand constrictor muscles and the innerlayer forms pigmented epithelium;the ectomesenchyme of the iris formsa pupillary membrane that conveysan anterior blood supply to thedeveloping lens; when the membranedegenerates following developmentof the lens, a pupil is formed;

— the cornea develops fromtwo sources: the layer ofectomesenchyme that forms sclera isinduced by the lens to become innerepithelium and stroma of the cornea,while surface ectoderm forms theouter epithelium of the cornea; theanterior chamber of the eye developsas a cleft in the ectomesenchymesituated between the cornea and thelens;

— the eyelids are formed by upper and lower folds of ectoderm, each fold includes a mesen-chyme core; the folds adhere to one another but they ultimately separate either prenatally (ungulates)or approximately two weeks postnatally (carnivores); ectoderm lining the inner surfaces of the foldsbecomes conjunctiva, and lacrimal glands develop by budding of conjunctival ectoderm;

— skeletal muscles that move the eye (extraocular eye mm.) are derived from rostralsomitomeres (innervated by cranial nerves III, IV, and VI).

Clinical considerations: • The ungulate retina is mature at birth, but the carnivore retina does not fully mature until about 5weeks postnatally. • Retinal detachment occurs between the neural and outer pigmented layers of the retina (innerand outer walls of the optic cup) which do not fuse but are held apposed by pressure of thevitreous body.• Coloboma is a defect due to failure of the optic fissure to close. • Microphthalmia (small eye) results from failure of the vitreous body to exert sufficient pressurefor growth, often because a coloboma allowed vitreous material to escape.• Persistent pupillary membrane results when the pupillary membrane fails to degenerate andproduce a pupil.

Anterior Eyeball and Eyelidslacrimalgland

optic cup

vitreouscompartment

hyaloidartery

ciliarybody

iris

lens

pupillarymembrane

anteriorcompartment

cornea

dorsaleyelid

conjunctivalsac

64

Formation of the EarThe ear has three components: external ear, middle ear, and inner ear. The inner ear contains

sense organs for hearing (cochlea) and detecting head acceleration (vestibular apparatus), the latter isimportant in balance. Innervation is from the cochlear and vestibular divisions of the VIII cranial nerve. Themiddle ear contains bones (ossicles) that convey vibrations from the tympanic membrane (ear drum)to the inner ear. The outer ear channels sound waves to the tympanic membrane.

Inner ear:— an otic placode develops in surface ectoderm adjacent to the hindbrain; the placode

invaginates to form a cup which then closes and separates from the ectoderm, forming an otic vesicle(otocyst); an otic capsule, composed of cartilage, surrounds the otocyst;

— some cells of the placode and vesicle become neuroblasts and form afferent neurons of thevestibulocochlear nerve (VIII);

— the otic vesicle undergoes differential growth to form the cochlear and semicircular ductsof the membranous labyrinth; some cells of the labyrinth become specialized receptor cells of maculae and

ampullae;

vestibular apparatus

cochlea

oticvesicle

Inner EarDevelopment

outerear

tympanicmembrane

ossciles(bones)

BRAIN

vestibulocochlearnerve

cochlea

auditory tube (to nasopharynx)

innerear

middleear EAR

(in section)

65

— the cartilagenous otic capsule undergoes similar differential growth to form the osseouslabyrinth within the future petrous part of the temporal bone.

Middle ear:— the dorsal part of the first pharyngeal pouch

forms the lining of the auditory tube and tympanic cavity(in the horse a dilation of the auditory tube develops into the gutturalpouch);

— the malleus and incus develop as endochondralbones from ectomesenchyme in the first branchial archand the stapes develops similarly from the second arch (infish, these three bones have different names; they are larger andfunction as jaw bones).

Outer ear:— the tympanic membrane is formed by apposi-

tion of endoderm and ectoderm where the first pharyngealpouch is apposed to the groove between the first andsecond branchial arches;

— the external ear canal (meatus) is formed by the groove between the first and secondbranchial arches; the arches expand laterally to form the wall of the canal and the auricle (pinna) ofthe external ear.

Taste budsTaste buds are groups of specialized (chemoreceptive) epithelial cells localized principally

on papillae of the tongue. Afferent innervation is necessary to induce taste bud formation andmaintain taste buds. Cranial nerves VII (rostral two-thirds of tongue) and IX (caudal third of tongue) innervate the

taste buds of the tongue.

OlfactionOlfaction (smell) involves olfactory mucosa located caudally in the nasal cavity and the

vomeronasal organ located rostrally on the floor of the nasal cavity. Olfactory neurons are chemore-ceptive; their axons form olfactory nerves (I).

— an olfactory (nasal) placode appears bilaterally as an ectodermal thickening at the rostralend of the future upper jaw; the placode invaginates to form a nasal pit that develops into a nasalcavity as the surrounding tissue grows outward; in the caudal part of the cavity, some epithelial cellsdifferentiate into olfactory neurons;

— the vomeronasal organ develops as an outgrowth of nasal epithelium that forms a blindtube; some epithelial cells of the tube differentiate into chemoreceptive neurons.

Auditory Tube Formation

oticvesicle

externalauditorymeatus

tympanicmembrane

middle earauditory tube

pharynx

HINDBRAIN

66

Appendix IGametogenesis

Germ cells provide the continuity of life between generations of a species, by passing onchromosomal DNA which contains developmental information for the species. Diploid (2N) germcells are capable of producing haploid (1N) gametes. Fusion of haploid gametes produces a diploidzygote (the beginning of a new individual of the species).

Note: N = the number of pairs of chromosomes, i.e., the number of chromosomes each parent contributes to the

new individual.

Gametogenesis . . . refers to the formation of haploid (1N) gametes (sperm or oocytes) by diploid (2N) germ

cells (primary spermatocytes or primary oocytes) through a process called meiosis.

Spermatogenesis (duration varies: 34 days in mouse; 36 days in stallion; 74 days in human)

• spermatocytogenesis

— spermatogonia (2N) proliferate, producing themselves & primary spermatocytes (2N)

— primary spermatocyte (2N) produces two secondary spermatocytes (1N) via Meiosis I

— two secondary spermatocytes (1N) divide into four spermatids (1N) via Meiosis II

• spermiogenesis

— transformation of a spermatid into a sperm (spermatozoon) cell (duration 18 days)

Oogenesis (duration: from before birth to some time between puberty and loss of fertility)

— oogonia (2N) proliferate themselves and primary oocytes (2N) in the embryo & fetus

— primary oocyte (2N) remains in prophase of Meiosis I until it is ovulated;

then, it divides into a secondary oocyte (1N) and a polar body (1N)

— following fusion with sperm , the secondary oocyte (1N) completes Meiosis II;

the result is a fertilized ovum or zygote (now 2N)

NOTE: Following Meiosis I, all of the oocyte cytoplasm becomes associated with just one of thedaughter cells, called a secondary oocyte. The other daughter cell (nucleus) is called a polar body.Following Meiosis II, all of the oocyte cytoplasm becomes associated with just one of thedaughter cells, called an ovum. The other daughter cell (nucleus) is called a polar body. Since thefirst polar body also undergoes Meiosis II, a total of three polar bodies are produced by meiosis.

germ cells

zygote

embryo

adultLife

Cycle

67

Gametogenesis

Spermatogenesis (formation of spermatozoa)

A] Spermatocytogenesis (formation of spermatids in seminiferous tubules)

primordialgerm cells

spermatogonia (2N)

primary spermatocyte (2N)

two secondary spermatocytes (N)

four spermatids (each N)

mitosis (throughout post-puberty)

B] Spermiogenesis (transformation of spermatids to spermazoa) — elongate nucleus, loss of cytoplasm & cytoplasmic bridges, formation of acrosome & tail — transformation occurs while linked to a Sertoli cell — spermatozoa are release into lumen of seminiferous tubule

Oogenesis (formation of an ovum)

birth

(oocyte in primordial follicle, surrounded by flat follicular cells)

prophase, etc. of Meiosis I completed

Meiosis II

Meiosis I

primary oocytes (2N) in prophase of meiosis I

puberty(selected follicles/estrus)

ovulation

spermatozoan (N)

Meiosis II completed(NOTE: horse & dog sperm unite with

a primary vs a secondary oocyte)

Note: Fertilization begins with union of male and female gametes and ends with the start of zygote cell division (cleavage).

primordialgerm cells

oogonia (2N)mitosis (occurs only in an embryo)

secondary oocyte (N) + first polar body

fertilized ovum (2N zygote) + second polar body

(oocyte in primary follicle, surrounded by cuboidal follicular cells)

(oocyte in secondary & tertiary follicles, surrounded by zona pellucida, layersof follicular cells, and fluid chamber)

(germ stem cells) incomplete cell division(cytoplasmic bridges)

68

Appendix IIMitosis and Meiosis

Somatic Cell Cycle and Cell Division (Mitosis):

Interphase:period prior to DNA synthesis [G1 = days or G0 = very long time];period of DNA synthesis [S = 10 hrs.];period of preparation for mitosis [G2 = 1 hr].

Synthesis = each double-stranded helix of DNA (one chromatid/chromosome) becomestwo double-stranded helicies of DNA (two chromatids/chromosome).

Mitosis = cell division where each of two daughter cells receives chromosomalmaterial identical to the parent cell (i.e., one of two chromatids per chromosome).

Stages of mitosis:Prophase — chromosomes become visible and the nuclear membrane disappears

under the light microscope (90 min.) ;Metaphase — individual, double-chromatid chromosomes align randomly at the equatorial

region between centrioles (30 min.) ;Anaphase — the two chromatids per chromosome separate as the centromere divides and

each chromatid becomes a chromosome in a new nucleus (5 min.) ;Telophase — chromosomes become invisible and the nuclear membrane reappears

interphase(one chromatid/chromosome)

interphase(synthesis)

mitosis

Somatic Cell

Cycle

(two chromatids/chromosome)interphase

69

Diploid Somatic Cell

telophaseof aprecedingmitoticdivision

chromosomesare uncoiled

&DNA

synthesis is taking place

Mitosis

from Mom

from Dad

Prophase Metaphase

AnaphaseTelophase

individualchromosomesalign atequator

2 chromatidsper

chromosomelinked by a

centromere

individual chromatids separate & each goes to a daughter cell

Two identical daughter cells (diploid)

cytoplasm

nucleus

Interphase

70

Germ cell division:A diploid germ cell

initially undergoes Meiosis I,a reduction division: [2N —>2(1N)].

Then each of twohaploid daughter cells under-goes Meiosis II, a mitotic-likedivision.

Four gametes (fourspermatids or one ovum plusthree polar bodies) are produced.

Meiosis: (following interphase in which DNA synthesis occurs)Meiosis I (reduction division: one diploid —> two haploid cells)

Prophase— chromosomes become visible (as paired chromatids joined at centromeres)— homologous chromosomes are paired (linked by a synaptonemal complex) Note: chromatids of linked homologous chromosomes may exchange comparable DNA,

i.e., exchange genes (genetic cross-over)Metaphase

— homologous chromosome pairs align at equatorial region between centriolesAnaphase

— homologous chromosome pairs separate (one chromosome of a pairmoves toward one centriole and the other toward the other centriole).

Note: haploid daughter cells inherit different assortments of maternal/paternal chromosomes.The number of possible assortments = 2N, where N = number of chromosomes/gamete,e.g., for human 223 = over 8 million. Including cross-overs = incalculable variety.

Telophase— chromosomes become less visible;

nuclear membrane reappears; cytoplasm division occurs.

Meiosis II (mitosis-like division of each haploid cell)Prophase

— chromosomes visible (very brief period)

Metaphase— individual chromosomes align at equatorial

region between centrioles.Anaphase

— the two chromatids per chromosomeseparate at the centromere region

— each chromatid moves toward itsrespective centriole and becomes a chromosome in anew nucleus

Telophase— chromosomes become less visible; nuclear membrane reappears; cytoplasm divi-

sion occurs (cytokinesis).

meiosis I I

two gametes(sperm or ovum)haploid with one

chromatid/chromosome Germ Cell

Cycle

(two chromatids/chromosome)diploid germ cell

meiosis I

haploid germ cell(two chromatids/chromosome)

Crossover during Meiosis I

paternalchromatids

maternal chromatids

centromere

synaptonemalcomplex

Homolgous Chromosome Pair

maternal/paternalgenetic exchange

71

Primary spematocyte or oocyte(diploid germ cell)

telophaseof aprecedingmitoticdivision

chromosomesare uncoiled

&DNA

synthesis is taking place

Meiosis I

Meiosis II

from Mom

from Dad

Prophase Metaphase

AnaphaseTelophase

homologouschromosomepairsalign atequator

2 chromatidsper

chromosome &

homologous chromosomes

linked together

homologouspairs separate& either homologuschromosomegoes to adaughter cell

Prophase Metaphase Anaphase Telophase

Prophase

2N1N

Secondary spermatocytes or oocytes (haploid)

MetaphaseAnaphaseTelophase

Gametes(sperm or ova)

Gametes(sperm or ova)

cytoplasm

nucleus

Interphase

72

Appendix IIICongenital Anomalies of Clinical Significance

(See also Noden and De Lahunta, Embryology of Domestic Animals)

This is a small representation of the many anomalies which can occur. It is presented here tostimulate an awareness in practitioners-to-be to that congenital malformations are etiological factorsto be considered in making differential diagnoses

A. Placentation:

1. Hydrops of the amnion or allantois.Accumulation if excessive fluid in either amniotic or allantoic cavities results in fetal death.

If not relieved, in late pregnancy they can cause uterine or prepubic tendon rupture. Progressivebilateral abdominal distention, anorexia, and recumbency are signs of their occurrence.

2. Strangulation by umbilical cord.In species with long umbilical cords, e.g., swine, neck or limb strangulation in varying

degree may occur.

B. Face, mouth, nasal cavity, and pharynx.

1. Cheiloschesis (cleft lip), palatoschisis (cleft palate).Cleft lip is caused by failure of fusion of medial nasal and maxillary processes; cleft palate is

caused by failure of medial palatine processes to fuse.

2. Branchial cyst (no opening), branchial sinus (opening to exterior), branchial fistula(openings to interior and exterior).

These result from failure of involution of the branchial apparatus caudal to branchial arch II.Cysts and sinuses are minor problems, and can be surgically relieved.

3. Heterotopic polyodontia (dentigerous cyst, “ear teeth”).Primordia of enamel organs escape to the exterior and develop tooth structures anchored on

the parietal bone or base of the ear. These cause festering problems and must be relieved surgically.

4. Thyroglossal duct cyst.Failure of involution of thyroglossal duct is the cause. A surgically removable fluid-filled

cyst seen at birth interferes with breathing.

73

C. Digestive tract.

1. Meckel’s diverticulum.Persistence, inflammation, and rupture of this structure, which is an appendix-like remnant

of the yolk stalk, results in colic, with peritonitis.

2. Atresia of the jejunum, ileum, colon, rectum.A lack of epithelial canalization and gut wall development results in feed impaction and

death if surgical intervention cannot be made. Some evidence suggests that one cause is manualmanipulataion of fetal membranes rectally in pregnancy diagnosis.

3. Imperforate anus.This results from lack of involution of the cloacal membrane, and leads to fatal feed impac-

tion. Where anal musculature is developed, surgical removal of the cloacal membrane offers tempo-rary if not permanent relief.

D. Lower respiratory tract.

1. Tracheoesophageal fistula.This results from a partial persistence of the laryngotracheal groove. Its presence in the

newborn causes refluxing of feed through the upper respiratory tract, and inhalation pneumonia.Surgical treatment is difficult.

2. Barker foal syndrome: hyalin disease. This is believed to result from a lack of production of pulmonary surfactant, which may be

temporary. Gasping of the newborn is a sign of its presence.

E Heart and arterial system.

1. Ectopia cordis.Here the heart remains in the cervical region where it was formed embryologically. Though

some animals survive to adulthood, they become unthrifty.

2. Intertrial septal defect (ASD); interventricular septal defect (VSD).An unthrifty animal usually results.

3. Tetrology of Fallot.Three primary abnormalities are: ventricular septal defect; shift of left ventricular outflow to

the right; and pulmonary stenosis.A resulting fourth abnormality is a hypertrophy of the right ventricle.

4. Persistent truncus arteriosus.This is due to a partialor complete lack of formation and fusion of truncus spiral ridges.

Depending upon the severity of malformation, cyanosis and fatigue, poor growth, and death mayoccur.

74

5. Persistent ductur arteriosus.Failure of closure at birth results in the so-called blue baby condition, wherein poorly oxy-

genated blood is delivered to the whole body except the head, neck, and right fore appendage re-gions.

6. Right aortic arch.The left aortic arch normally forms the ascending aorta; an anomalous right arch, together

with the normal left ductus arteriosus (ligamentum arteriosum), forms a strangualting vascular ringaround the esophagus and trachea. Inability to swallow solid feed in young animals is a first symp-tom.

7. Ectopic right subclavian artery.Origin of the right subclavian artery from the ascending aorta instead of the brachiocaphalic

trunk also results in a strangulation of the esophagus and trachea.

8. Persistent vitelloumbilical band.Especially in equidae where there is a well developed yolk sac, the left vitelline artery and

yolk stalk may persist, forming a band between the ileum and umbilicus. Intestinal strangulationmay result. Development of colic is a first symptom.

F. Venous and lymphatic systems.

1. Portosystemic shunts.Venous return from the gut should first pass through the liver since it contains toxic substances

normally metabolized in the liver. One anomaly which prevents this return is an anomalous persist-ing ductus venosus. The other is a central or peripheral portal-venous shunt to the caudal venacava or azygous vein. Both result in young animals showing abnormal nervous behavior as a firstsymptom.

2. Congenital hereditary lymphoedema.Absence of lymph vascular connections to the venous system result in edema of the involved

body regions.

G. Body cavities.

1. Pleuroperitoneal hernia.Failure of closure of one or both pleuroperitoneal folds results in intestinal herniation into the

pleural cavity. Labored breathing is a symptom.

2.Peritoneopericardial diaphragmatic hernia.During fetal development the liver dissects away from the transverse septum, occasionally

leaving a central weakness in the fibrous part of the diaphragm. Intestinal herniation through thisarea into the pericardial sac will result in abnormal cardiac sounds and dyspnoea.

75

H. Urinary and genital systems.

Three facts render the urogenital system vulnerable to anomalies, as follows: 1), they arisein part by by faulty division of the cloaca;into rectum and urogenital sinus; 2), in both sexes, espe-cially the male, part of the urinary tract is co-opted during fetal development for use in the forma-tion of the internal genital system; and 3), there is a marked translocation of urinary and reproduc-tive duct terminals during fetal development.

1. Ectopic ureter.Entry of the ureters into the vagina or urethra results in dribbling of urine and bladder infec-

tion. Hydronephrosis may also result due to blockage of terminal ureteral orifices.

2. Urorectal fistula: rectovesicular, rectovestibular, rectourethral.Due to faulty separation of the cloaca into rectum and urogenital sinus a fistulous tract may

remain. This leads to abnormal elimination of urine and feces, and urinary tract infection.

3. Patent urachus.The urachus is the urinary canal of the fetus. It becomes the median ligament of the bladder.

Moistness or dribbling of urine at theumbilicus following birth results if it remains patent.

4. Double cervix.This results from lack of fusion of the paramesonephric ducts beyond the body of the uterus.

It may present parturition difficulties.

5 Paramesonephric duct atresia (White heifer disease).This consists of the absence of the paramesonephric duct derived parts of the female tract

(oviducts, uterus, cervix, and vagina). Ovaries are normal. The cause is known; it is not limited towhite cattle.

6. Hypospadia.Failure of urethral folds to fuse results in an opening of the urethra on the ventral surface of

the penis

I. Nervous system.

Aganglionosis.This results from lack of migration of neural crest cells to form intestinal ganglia. This

condition, seen especially in Overo spotted horses, results in a flaccid, atonic large intestine. It isfatal for newborn animals due tointestinal impaction.

76

J. Musculoskeletal system.

1. Premature physeal closure (achondroplasia, chondrodysplasia).This may be a generalized anomaly of the appendages, or involve one of the long bones. In

the latter instance, normal appendage use can be restored through orthopedic surgery. The cause isunknown.

2. Spina bifida.This results from a failure of the vertebral arch to form dorsally over the vertebral canal. It

usually occurs in the lumbar and sacral regions, and may interfere with locomotion.

3. Flexural and angular limb deformities (arthrogryposis).These occur most frequently in equidae. Preliminary investigations indicate that autosomal

trisomy of one of the smaller chromosomes is associated with their appearance.