Open AccessMolecular Dynamics of Retinoic Acid-Induced Craniofacial Malformations: Implications for the Origin of Gnathostome Jaws
Author(s) -
Maxence Vieux-Rochas,
Laurent Coen,
Takahiro Sato,
Yukiko Kurihara,
Yorick Gitton,
Ottavia Barbieri,
Karine Le Blay,
Giorgio R. Merlo,
Marc Ekker,
Hiroki Kurihara,
Philippe Janvier,
Giovanni Levi
Publication year - 2007
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0000510
Subject(s) - craniofacial , retinoic acid , biology , neural crest , fgf8 , endoderm , anatomy , morphogenesis , microbiology and biotechnology , medicine , endocrinology , genetics , receptor , cellular differentiation , embryo , gene , fibroblast growth factor
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 RARß-dependent mechanism. Methodology/Principal Findings 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/Significance 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.