Molecular dynamics of retinoic acid-induced craniofacial malformations: implications for the origin of gnathostome jaws.
BACKGROUND
Intake of retinoic acid (RA) or of its precursor, vitamin A, during early pregnancy is associated with increased incidence of craniofacial lesions. The origin of these teratogenic effects remains enigmatic as in cranial neural crest cells (CNCCs), which largely contribute to craniofacial structures, the RA-transduction pathway is not active. Recent results suggest that RA could act on the endoderm of the first pharyngeal arch (1stPA), through a RARbeta-dependent mechanism.


RESULTS
Here we show that RA provokes dramatically different craniofacial malformations when administered at slightly different developmental times within a narrow temporal interval corresponding to the colonization of the 1(st) PA by CNCCs. We provide evidence showing that RA acts on the signalling epithelium of the 1(st) PA, gradually reducing the expression of endothelin-1 and Fgf8. These two molecular signals are instrumental in activating Dlx genes in incoming CNCCs, thereby triggering the morphogenetic programs, which specify different jaw elements.


CONCLUSIONS
The anatomical series induced by RA-treatments at different developmental times parallels, at least in some instances, the supposed origin of modern jaws (e.g., the fate of the incus). Our results might provide a conceptual framework for the rise of jaw morphotypes characteristic of gnathostomes.
Vieux-Rochas
Maxence
M
Evolution des Régulations Endocriniennes, CNRS, UMR5166, Muséum National d'Histoire Naturelle, Paris, France.
Coen
Laurent
L
Sato
Takahiro
T
Kurihara
Yukiko
Y
Gitton
Yorick
Y
Barbieri
Ottavia
O
Le Blay
Karine
K
Merlo
Giorgio
G
Ekker
Marc
M
Kurihara
Hiroki
H
Janvier
Philippe
P
Levi
Giovanni
G
D000818:Animals; D019465:Craniofacial Abnormalities / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D051767:Early Growth Response Protein 2 / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000502:physiology; D017403:In Situ Hybridization; D007568:Jaw / Q000033:anatomy & histology*; D007641:Keratolytic Agents / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D009432:Neural Crest / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*
C501120:Dlx5 protein, mouse; D051767:Early Growth Response Protein 2; D019332:Endothelin-1; D018398:Homeodomain Proteins; D007641:Keratolytic Agents; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin