Maxillofacial Embryology And Development

Maxillofacial embryology and development

Heather Etchevers, Ph.D.

INSERM

Facialmodules

Developmentover time

Neural crestcontributions

Facialmalformations Summary

Defining some terms for orientation

“Germ layers” Ectoderm Mesoderm Endoderm (Neural crest)

Four dimensions Dorsoventral Rostrocaudal Mediolateral Time!!

Scanning EMHuman embryo, 24 dAll EM photos ©K Sulik and M Vekemans

Photo © A Thornton

Facialmodules




Embryonic constituents

Facialmodules




The five “fingers” of the face Medial

Frontonasal bud Medial Lateral

Bilaterally paired First pharyngeal arch

Maxillary Mandibular

Second pharyngeal arch Hyoid

Second and beyond will be part of neck

eye

human embryo, 28 days

Facialmodules




In the second month…

eye

Facialmodules




Growth of segments

Normal development = differential growth Controlled by cell behaviour

programmed death migration differentiation

Facialmodules




Skull components from facial buds

Couly et al. (1993) Development 117:409

Facialmodules




Rostrocaudal axis recapitulates temporal maturation

24 days

future face and head

Facialmodules




embryo

Endoderm

Facialmodules




The pharyngeal arches

Metameric 5 in mammals Numbered historically 1-4, 6

Epithelia Outer, lateral ectodermal bulges Inner, medial endodermal pouches Meet as membranous grooves

Mesenchyme Mesodermal core (artery and muscle) Neural crest cells (everything else)

Facialmodules




Facialmodules




Cephalic neural crest mesectodermal derivatives

Support tissues for pituitary, salivary and lachrymal glandsTendons for cephalic muscles

dermisadipose tissuecartilageboneperiostdura materpia materpericytes brain

epidermis

Facialmodules




Neural crest cells fill out the facial buds

Facialmodules




Fate-mapping with chick-quail chimeras

Couly and Le Douarin

Facialmodules




Poulet E8

r6r5r4

r3r2r1

PD,AM,PM

Sturge-Weber syndrome

Segmental distribution of progeny in some disease

Etchevers et al. (2001)

Facialmodules




Regulation of cell behavior by diffusible signals

Initiators of protein signalling cascades Membrane Cytoplasmic second messengers Transcription factor activation or repression Target transcription or inactivation

Physiological role for known oncogenic pathways FGF, Wnt, Notch/Delta, EGF, Shh…

Facialmodules




Congenital craniofacial malformations

Over 700 of the approx 5,000 known inherited conditions affect the craniofacial area

1/3 of birth defects have CF malformations Many of these perturb signals directing neural

crest Migration Proliferation or programmed cell death Differentiation

Facialmodules




Cleft lip/palate Physiological cleft lip until 6-7 weeks Approx 1 per 800-1,000 births Genetic component to cleft lip ± palate

More frequent in some populations More frequent in males 20% associated with ~100 genetic syndromes

Physiological cleft palate until 10 weeks No racial predominance but females > males Isolated = approx 1 per 2,000 births 50% syndromic

Facialmodules




Clefts at 7 weeks’ development

eye

Facialmodules




Facial clefting

Wilkie and Morris-Kay, 2001

Maxillary budderivatives

Facialmodules




DiGeorge syndrome

More frequent cleft lip/palate Small jaw Small upper lip/mouth Eyes slanted upward or downward Low-set and/or abnormal folding of ears Short stature, mild to moderate learning

difficulties Underdeveloped parathyroid and thymus Cardiac malformations

Digilio et al., 2005

Facialmodules




Tbx1 knockout mouse phenocopies DGS patients

Jerome and Papaioannou, 2001

Bindingsite

Target gene

Transcriptionfactor

RNA, then protein

Facialmodules




from S. Lyonnet

Del22q11.2 – often but not always TBX1 itself: distant regulation

Aided and abetted by a polymorphism 1Kb upstream of VEGF !Stalmans et al., 2003

Facialmodules




The holoprosencephaly spectrum

Wilkie and Morris-Kay, 2001; image from Muenke, M. & Beachy, P. A. in The Metabolic and Molecular Bases of Inherited Disease 8th edn (eds Scriver, C. R. et al.) 6203–6230 (McGraw–Hill, New York, 2001).

proboscis

Single median incisorNo philtrum

Facialmodules




Cell signaling via hedgehog family

after van Tuyl et Post., 2002

Patched

Sonic/Indian hedgehog

Gli and Zic TF genes

cyclopamine

Facialmodules




Neural crest ablation can phenocopy lack of Shh

Normal 8d chicken embryo Neural crest-ablated chicken embryos

Facialmodules




Primary cilia transduce Sonic hedgehog signaling

Rohatgi, R., Milenkovic, L. and Scott, M.P. (2007). Science, 317, 372–376.

Photo from PKD group, Mayo Clinic; figure adapted from Kibar et al., Clin Genet 2007

Cilium

PK

VANGL FZ

WN

TsINV

DVL

SCRIB

DAAM

RHOA

JNK

FYIN

ROCK

SHH

PTCH

Cytoskeletal changes Transcriptional changes

PTK7

actins

BBS

CELSR

Facialmodules




Midline facial disorders arise from defects in primary cilia

Figure 9 from Brugmann et al., Human Molecular Genetics 2010, Vol. 19, No. 8

1577–1592 doi:10.1093/hmg/ddq030After Wilder

Facialmodules




Key points

The pharyngeal arches are metameric structures containing tissues from all germ layers

The upper lip and palate are subject to clefts because of facial fusion of frontonasal and maxillary tissues during development

Multipotent neural crest mesenchyme is a major structural component of the face

Facialmodules




I will make this Powerpoint presentation available and downloadable as of next week on SlideShare, but you also have it available as part of this course.

http://www.slideshare.net/Alethea

Please comply with fair use (cf Wikipedia if you need to) as the images and photographs are copyrighted by their authors. I will correct any lacunae in attributions if you leave a comment.

Health & Medicine

Maxillofacial Embryology And Development