Neuroembryology

Developmental Organization of the

Nervous System:

NeuroembryologyNeuroembryology

Overview

• Provides framework and background for understanding

the anatomy of the nervous system in the adult

• Serves as an aid in understanding the pathogenesis of

developmental neurologic abnormalities that are

encountered not only in the newborn and pediatric

periods but also in later life

Stages and timing of development of the nervous system.

Note that there is partial temporal overlap of the different

processes.

• Neural development is controlled by soluble signals

from the mesoderm, target-derived growth factors,

and adhesion molecules

• These substances control the expression of

transcription factors that regulate genes involved intranscription factors that regulate genes involved in

determining neuronal or glial fates

• These substances also control the dynamics of

cytoskeletal proteins required for axonal & dendritic

growth

Signals involved in the development of the nervous system. Formation of the neural plate and neural tube

Neural Plate

Neural Fold

Closure of Neural

Tube

Formation of Neural Tube

• The CNS of vertebrates arises from the dorsal

midline ectoderm of the vertebrate gastrula

• Neural Induction - transformation of these • Neural Induction - transformation of these

ectodermal cells into neural cells

- results in the formation of the neural

plate

• The neural tube is formed in 7 to 10 days, beginning

on the 18th day of gestation

• Primary neurulation - formation of the neural tube

as far caudally as the future S2 level

• Secondary neurulation - process whereby cavity of

neural tube extends into the caudal eminence

- gives rise to lower sacral cord, conus

medullaris, & filum terminale

• Neural induction involves the activity of an

organizer, Hensen node

• Anterior visceral endoderm - underlies the future

neural plate, is required for induction of the

formation of the forebrain

• Induction and patterning of NS occur in several

stepssteps

- during a first step, the anterior visceral endoderm and

precursors of the node elicit early neural induction

and specify the forebrain

- during a final step called caudalization, or

posteriorization,signals from the node specify the

midbrain, hindbrain, orspinal cord

• 18th day of gestation

- formation of neural tube begins

- early stage of gastrulation is completed

- 2-layered embryo consisting of ectoderm &

endoderm is transformed into a 3-layered

structure by the outgrowth of mesoderm from structure by the outgrowth of mesoderm from

the midline primitive streak

• Notochord

- grows forward from the anterior end of the

primitive streak (Hensen’s node)

Neural Plate

- formed from

induction of the

ectoderm overlying ectoderm overlying

the notochord

• Neural Groove

- lateral edges of

neural plate thicken

more rapidly than

the center, begin to

roll toward the

midlinemidline

• Neural Folds

• Neural Tube

- closes first in the

middle of the

embryo

• Neuropores

Neural Crest

- cell columns

- derived from the

junction of skin

ectoderm &

neuroectodermneuroectoderm

separate from the

neural tube & form a

major portion of the

PNS

Somites

- aggregation of

mesodermal cells

- bone & muscle arise- bone & muscle arise

• Primary brain vesicles:

- prosencephalon, mesencephalon, rhombencephalon

- further differentiate into 5 subdivisions

• Spinal cord

- formed from the remaining caudal end of the neural tube

Subdivisions of the primitive Nervous System

• The subdivisions of the neural tube are the

precursors of 3 of the 4 major anatomical levels in

the adult:

1. supratentorial (telencephalon, diencephalon)

2. posterior fossa (mesencephalon, metencephalon,

myelencephalon)

3. spinal (spinal cord)3. spinal (spinal cord)

4. peripheral level consists of a combination of

efferent fibers that grow out from the posterior

fossa & spinal levels & neural crest derivatives that

include somatic and visceral afferent neurons &

postganglionic autonomic neurons

Major Stages of Development and the Corresponding

Developmental Disorders • The neuroectodermal derivatives of the neural tube

& neural crest give rise to the sensory, motor,

internal regulation, and consciousness systems

• Mesodermal tissues surround the neural tube and

form the meninges, which in conjunction with the

ventricular system form the cerebrospinal fluid ventricular system form the cerebrospinal fluid

system

• Mesoderm that surrounds and grows into the neural

tube forms the vascular system

Cell Proliferation, Differentiation, Migration, and

Maturation

• Through 4 processes that occur in concert, the cells

that make up the mature nervous system:

1. accumulate in sufficient number

2. develop into the appropriate type of cells2. develop into the appropriate type of cells

3. move to specific sites

4. make specific connections with other cells

Cell Proliferation

• The wall of the primitive neural tube initially

consists of a single layer of neuroepithelial cells that

are derived from the ectoderm and form a

pseudostratified epitheliumpseudostratified epithelium

• These cells have an apical-basal polarity, with the

apical portion in contact with the central cavity and

the basal portion in contact with the outer surface

of the tube

• The primitive neural tube consists of ventricular, subventricular, and marginal zones

1. Ventricular Zone

- primary germinative zone and contains pluripotentneuroepithelial stem cells

- neuroepithelial cells of the ventricular zone are stem cells that give rise to progenitors of neurons and glialcells that accumulate in the subventricular zonecells that accumulate in the subventricular zone

2. Marginal Zone

- consists of the radially extended cytoplasmicprocesses of cells of the ventricular and subventricularzones

- radial glia, derived from neuroepithelial cells, may generate neurons during embryogenesis and then differentiate into mature astrocytes

• The primitive neural tube consists of

ventricular, subventricular, and marginal

zones:

3. Subventricular Zone3. Subventricular Zone

- adjacent to the lateral ventricles may

support neurogenesis in the adult brain

• Developmental Cell Death:

- many neuronal and glial precursors created

during the proliferative phase are removed

through programmed cell death, or apoptosisthrough programmed cell death, or apoptosis

- the main stimulus for programmed cell death

during development is deprivation of growth

factors

Differentiation of the cell layers in the primitive neural

tube

Differentiation of the Neural Tube

A. Longitudinal differentiation

- formation of forebrain, midbrain, hindbrain, and

brachial arches and placodes with closure of

neuroporesneuropores

B. Transverse differentiation of neural tube

- formation of alar plates (dorsolateral) and basal

plates (ventrolateral) separated by sulcus limitans

Longitudinal differentiation

• Even before the neural tube is entirely closed, longitudinal differentiation begins

• The cephalic, or head, end of the neural tube becomes larger than the caudal end, producing an becomes larger than the caudal end, producing an irregularly shaped tubal structure

• Continued differential growth along the length of the neural tube results in the formation of three cavities at the cephalic end of the tube

• The central cavity of the neural tube remains as the ventricular system

Longitudinal differentiation

1. Prosencephalon

- forms telencephalon and diencephalon

- Telencephalon:

dorsal zone - cerebral cortex

ventral zone - basal ganglia

- Diencephalon:- Diencephalon:

thalamus, hypothalamus, optic nerves, & pineal gland

2. Mesencephalon - forms the midbrain

3. Rhombencephalon

- forms metencephalon and myelencephalon

- Metencephalon - pons & granule cells of cerebellum

- Myelencephalon - medulla

Derivatives of the Neural Tube and Neural Crest

Transverse differentiation

• As the neural tube enlarges and rostrocaudal

patterning occurs, the neural tube undergoes

anatomic and functional differentiation in the

transverse planetransverse plane

• In a transverse section, the region of the neural tube

nearest the thoracic and abdominal cavities is

described as ventral and the region farthest from

them, as dorsal


• The differential proliferation of cells in the dorsal

and ventral regions on each side results in the

formation of a longitudinal groove, the sulcus

limitanslimitans

• The sulcus limitans divides the neural tube into a

dorsal region, or alar plate, and a ventral region, or

basal plate


• Alar plates give rise to afferent sensory structures in the

brainstem and spinal cord, including dorsal horns

- neurons receive peripheral sensory information from

derivatives of the somites (i.e., skin,muscle, joints, and

bone) or the endoderm (i.e., internal organs) and relay

this information to higher levels of the CNSthis information to higher levels of the CNS

• AFFERENT is used to describe nerve fibers that conduct

information from the periphery toward the CNS

• These neurons & pathways constitute the SENSORY

SYSTEM


• The growth of the alar plate of the prosencephalon

results in large cerebral hemispheres,which almost

completely surround the derivatives of the

diencephalon

• The cerebral cortex, basal ganglia, and thalamus are

all derived from the alar plateall derived from the alar plate

• The cerebellum arises from the proliferation of cells

of the alar plate, called the rhombic lip, in the

metencephalon and eventually covers the dorsal

surface of the entire rhombencephalon


• The basal plate gives rise to the motor neurons of

the BS and spinal cord

• These neurons are EFFERENT - they conduct

impulses away from the CNS

• Motor neurons and pathways concerned with the • Motor neurons and pathways concerned with the

control of striated skeletal muscle constitute the

somatic motor system

• Those concerned with the control of internal organs

form the visceral motor system

• The basal plate of the diencephalon gives rise to the

hypothalamus, posterior pituitary, & optic nerve

Transverse differentiation of the Neural Tube


• • As a consequence of transverse differentiation, the neural tube has a dorsal region, the alar plate, and a ventral region, the basal plate

• Alar plate

- gives rise to all sensory neurons, cerebellum, and cerebral hemispherescerebral hemispheres

• Basal plate

- gives rise to motor neurons & hypothalamus

• Cavity of the neural tube forms the central canal at the spinal cord level and more complex fluid-filled spaces, the ventricular system, at cephalic levels

• Cell columns called the neural crest separate from

the neural tube and form a major portion of the

peripheral nervous system

• Cells of the neural crest differentiate into DRG,

autonomic ganglia, & Schwann cells (peripheral glia)autonomic ganglia, & Schwann cells (peripheral glia)

• Cranial nerves are derived from both the neural

crest & specialized regions of ectoderm called

placodes

• Primitive neuroectodermal cells proliferate &

differentiate into neurons, astrocytes,

oligodendrocytes, & ependymal cells

• Neuronal precursors (neuroblasts) migrate to their

genetically coded location, guided by adhesion

molecules & glial cells

• Axons grow toward their targets and establish

specific synaptic connections with the appropriate

neurons

• These connections are stabilized by the activity of

the synapse and the presence of target-derived

factors

Neural Tube Defects

• Multifactorial disorders

• Risk factors: family history, maternal risk factors

(obesity, diabetes mellitus, hyperthermia, use of

anticonvulsants, folate deficiency)

• Detected by increased levels of α-fetoprotein (AFP) • Detected by increased levels of α-fetoprotein (AFP)

in maternal serum

• If serum AFP is increased, ultrasonography is

performed and amniotic fluid checked for AFP

Types of Neural Tube Defects

A. Craniorachischisis

- congenital malformations of CNS due to defective neural tube closure during 1st trimester of pregnancy producing contiguous exposure of brain & spinal column

B. AnencephalyB. Anencephaly

- absence of a major portion of the brain, skull, and scalp

- due to failure of anterior neuropore closure; defective notochord induction of the neuroectoderm

C. Meningomyelocele (spina bifida cystica)

- herniatio

D. Spina bifida occulta

- defect in 1 or more vertebral arches

- spinal cord & meninges are normal

E. Cranium bifidum

- defective fusion of cranial bones --> occipital - defective fusion of cranial bones --> occipital portion of the cranium

- associated with herniated cerebral tissue and meninges

F. Encephalocele

- extension of intracranial structures through

the cranial vault from a defect in fusion of

cranial bones

Meningocele - herniated meninges through skull

defectdefect

Meningoencephalocele - herniated brain tissue

and meninges through skull defect

Meningohydrocephalocele - herniated brain

tissue, meninges, and ventricles through skull

defect

Anencephaly Meningomyelocele

Myelomeningocele (spina bifida cystica)

- is herniation of the spinal cord and meninges

through a congenital defect in the vertebral arch. It

is covered with skin.

Cervical spina bifida, associated with Chiari type I

malformation. This needs to be differentiated from

Chiari type III malformation, which is essentially

herniated cerebellar and brainstem tissue.

Examples of failure of fusion at the spinal level.

Spina Bifida

• Cranium bifidum. Defective fusion of the

cranial bones, most commonly in the occipital

part of the cranium. In this example, note

herniation of the meninges with cerebrospinal herniation of the meninges with cerebrospinal

fluid only (meningocele).

• Occipital Encephalocele

• Frontal Encephalocele

Neuronal Migration

• In the developing nervous system, neurons migrate

from their site of origin in the germinal centers to

their final destination,where they mature and

develop functional connections

• Neuronal migration requires dynamic changes in the

neuronal cytoskeletonneuronal cytoskeleton

• It is guided by interactions between neurons and

the microenvironment, including glial cells and the

extracellular matrix

• These interactions are mediated by several adhesion

and guidance molecules

Radial Migration

• Radial migration is critical for the formation of

laminated structures such as the cerebral cortex

• Radial migration follows the radial organization of

the germinative zones in the neural tube and the germinative zones in the neural tube and

involves the radial glia,which provides a scaffold for

the directed migration of postmitotic neurons in the

brain

Radial migration is critical for the formation of the cerebral &

cerebellar cortices. Formation of the cerebral cortex involves

migration of precursors of pyramidal cells from the ventricular

zone to the periphery, toward the pial surface.

Tangential Migration

• Tangential migration of neural precursors from the

subventricular zone of the rostral forebrain is

important for development of the olfactory bulb

• Tangential migration is also involved in the

formation of the external granular cell layer of the formation of the external granular cell layer of the

cerebellum

• This is a secondary germinal matrix that originates

at the end of gestation and is the source of granule

cells in the cerebellum

Neuronal Maturation

• After a neuron has reached its final location in the

CNS, it establishes appropriate contacts with other

neurons, both locally and at a distance - by

extending processes called NEURITES

• Most neurites become dendrites,which receive • Most neurites become dendrites,which receive

information coming from other nerve cells

• The contact between the axon of a neuron and the

dendrites of the neuronal target is called a SYNAPSE

• Synapses are the basis for transmission of

information in the NS

Progressive neuronal differentiation involves

extension of dendrites and axons and formation of

synaptic contacts.

Neuronal Maturation

• Maturation of the nervous system involves

mechanisms of axonal growth, dendritic

development, and synaptogenesis

• These are dynamic processes that persist • These are dynamic processes that persist

throughout life and are critical for

mechanisms of learning and repair in the

nervous system

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Neuroembryology