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Molecular dynamics of retinoic acid-induced craniofacial malformations: implications for the origin of gnathostome
Maxence Vieux-Rochas1, Laurent Coen, Takahiro Sato
1Evolution des Régulations Endocriniennes, CNRS, UMR5166, Muséum National d'Histoire Naturelle, Paris, France.
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.
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.
Insights
Retinoic acid (RA) exposure during early pregnancy causes craniofacial malformations by altering gene expression in the first pharyngeal arch. This impacts jaw development and may explain the evolution of vertebrate jaws.
Area of Science:
- Developmental Biology
- Evolutionary Biology
- Teratology
Background:
- Maternal intake of retinoic acid (RA) or vitamin A during early pregnancy is linked to craniofacial lesions.
- The RA-transduction pathway is inactive in cranial neural crest cells (CNCCs), which form craniofacial structures.
- RA may affect the first pharyngeal arch (1stPA) endoderm via a RARbeta-dependent mechanism.
Purpose of the Study:
- To investigate the mechanism by which retinoic acid (RA) causes craniofacial malformations.
- To elucidate the role of RA in the development and evolution of jaw structures.
Main Methods:
- Administration of RA at precise developmental times during the colonization of the 1stPA by CNCCs.
- Analysis of craniofacial malformations induced by RA treatment.
- Assessment of RA's effect on endothelin-1 and Fgf8 gene expression in the 1stPA signalling epithelium.
Main Results:
- RA exposure at specific developmental windows causes distinct craniofacial malformations.
- RA reduces endothelin-1 and Fgf8 expression in the 1stPA signalling epithelium.
- These molecular signals are crucial for activating Dlx genes in CNCCs, directing jaw element specification.
Conclusions:
- RA's teratogenic effects on craniofacial development are mediated through the 1stPA signalling epithelium.
- The observed malformations induced by RA treatment parallel the evolutionary origins of jaw structures.
- These findings offer a framework for understanding the evolution of jaw morphotypes in gnathostomes.
