The importance of retinoic acid gradients and homeostasis for neural crest and craniofacial development

BACKGROUND: The development of the vertebrate face is regulated by a spatiotemporally precise, multistep developmental program initiated at the neural plate border by the specification of a unique population of cells, the neural crest. These cells will undergo epithelial-to-mesenchymal transition, migration in the pharyngeal arches, and differentiation into the skeletal elements of the face. RESULTS: Evidence from multiple organisms indicates that these processes are evolutionarily conserved and governed by core signaling pathways including BMP, Wnt, FGF, and retinoic acid (RA) that differentially regulate the expression of several families of transcription factors that are the effectors of the craniofacial developmental programs. CONCLUSIONS: In this review, we summarize the molecular mechanisms that regulate the different steps in neural crest and vertebrate craniofacial development and discuss the role of RA gradients and homeostasis in this context and the craniofacial pathologies associated with RA dysregulation.