The progression of v erteb rates from stem c h o rd a tes h a s
involved the diversification of fins an d lim bs, th e elaboration of the
endoskeleton, cephalization, increased sensory org an s a n d n eu ral
processing. In th e course of evolution early v erteb rates u n d e rw en t a
m ajor behavioural explosion an d sta rte d to occupy m ost ecological
dom ains, th e em ergence of th e first ch o rd ates, th e jaw less fish
coincided w ith the arrival of th e n e u ra l crest cells (N orthcutt an d
G ans 1983). These m u lti-p o ten t p rec u rso r cells originate from the
n e u ra l c rest after closure of th e n e u ra l tu b e in v erteb rate em bryos.
After closure of th e n e u ra l tu b e the n e u ra l crest cells m igrate an d
Medial nasal process Lateral nasal p ro cess Maxillary process Mandibular process Early 6th w eek Intermaxillary p rocess Late 7th w eek 10th w eek F ig u re 2 .3 E arly em b r y o n ic d e v e lo p m e n t an d fu s io n o f t h e fa c ia l p r o c e s s e s (m o d ified fro m L a rsen ’s H u m a n E m b ryology)
Cells a n d tis s u e s derived from th e n e u ra l c re s t in c lu d e th e
p e rip h e ra l n e rv o u s sy stem , e n d o crin e g lan d s, p ig m e n t cells, te e th ,
p h a ry n g e a l a rc h e s a n d m o st of th e b o n e s a n d cartila g e w h ic h m ak e
u p th e sk u ll a n d jaw . The c re st cell p o p u la tio n b eco m es m o re
h e te ro g e n e o u s w ith tim e a s th e cells m ig ra te v e n tra lly a n d e n c o u n te r
different co n d itio n s a t different sites. T he n e u ra l c re s t cells h av e a n
in -b u ilt d ev elo p m en tal m e c h a n ism for g e n e ra tin g a d iv ersity of cell
ty p es, cell a rra n g e m e n ts a n d c ap a city to re s p o n d to a w ide v ariety of
co n d itio n s. The c ra n ia l n e u ra l c re s t cells c a n also a d a p t to c h a n g e s in
th e size a n d sh a p e of th e b ra in , se n se o rg a n s a n d b ra n c h ia l a rc h e s a s
th ey all lie in th e ir m ig ratio n p a th (Le D o u a rin e t al 1994). R ecent
w o rk h a s sh o w n th a t c ra n ia l n e u ra l c re s t cells do n o t follow a fixed
p re d e te rm in e d p la n in p a tte rn in g of facial tis s u e s ; r a th e r, p a tte rn in g
is m a in ta in e d by p assiv e tra n s fe r of p o sitio n a l in fo rm a tio n from th e
h in d b ra in to th e p e rip h e ry (Trainor a n d K ru m la u f 2000).
The m o le cu la r g en etics of early n e u ra l c re s t fo rm atio n c a n be
se e n a s 3 m a in sta g e s (LaBonne a n d B ro n n e r-F ra s e r 1999). S tage one
is th e fo rm atio n of th e n e u ra l crest; th is involves th e c lo su re of th e
n e u ra l tu b e a n d re q u ire s th e in te ra c tio n of n u m e ro u s g en es in clu d in g
BMP, W nt, FGF, a n d MSX-1. The se co n d sta g e is th e e x p re ssio n of
g en es a t th e n e u ra l c re st w h ich e s ta b lis h th e p a tte rn in g a n d
m ig ra tio n fate of th e n e u ra l c re st cells, g e n es a c tin g a t th is stag e
stag e is n e u ra l c re st cell m ig ratio n w h ich involves g e n es s u c h a s Rho-
fam ily G T Pases a n d cell a d h e sio n m o lecu les s u c h a s c a d h e rin s .
C ra n ia l n e u ra l c re st cells m ig rate to p o p u la te th e first
b ra n c h ia l a rc h a n d ev en tu ally d ifferen tiate in to m u ltip le cell lineages
in th e m ax illa a n d m an d ib le d u rin g cran io facial m o rp h o g e n e s is . The
d ev elo p m en t a n d d ifferen tiatio n of n e u ra l c re s t cells w ith in th e
b ra n c h ia l a rc h e s relies u p o n th e actio n of n u m e ro u s tra n s c rip tio n
fac to rs w h ich guide m ig ra tin g cells a n d la te r p lay a role in lineage
d e te rm in a tio n e x p a n sio n a n d d ifferen tiatio n . M any g e n es h av e b een
re p o rte d to be involved in b ra n c h ia l a rc h d ev elo p m en t, D ix -1 a n d
D ix-2 (Qiu e t al 1997, T h o m as et al 2000), G oosecoid (B o u ch er e t al
2000), Fgf8 (T ucker et al 1999), E n d o th elin -1 a n d E n d o th e lin
re c e p to r A (C louthier et al 2000) hav e all rec en tly b e e n a s so c ia te d
w ith d efects in cep h alic n e u ra l c re s t derived sk e letal e le m e n ts. The
m an d ib le is p re d o m in a n tly affected a n d o v erlap p in g p h e n o ty p e s w ere
o b serv ed in th e k n o c k o u t a n im a ls s tu d ie d (zebraQ sh, m o u se a n d
c h ick ).
N orm al d ev elo p m en t of th e h e a d is th e r e s u lt of a n extrem ely
com plex se q u e n c e of tig h tly c o -o rd in a te d p a th w a y s d u rin g grow th
a n d m o rp h o g en e sis. At th e cell level, p o sitio n a n d tim in g a re critical
a n d sen sitiv e to p e rtu rb a tio n .