Abstract
Proper retinoic acid (RA) signaling is essential for normal craniofacial development. Both excessive RA and RA deficiency in early embryonic stage may lead to a variety of craniofacial malformations, for example, cleft palate, which have been investigated extensively. Dysregulated Wnt and Shh signaling were shown to underlie the pathogenesis of RA-induced craniofacial defects. In our present study, we showed a spatiotemporal-specific effect of RA signaling in regulating early development of facial prominences. Although inhibited Wnt activities was observed in E12.5/E13.5 mouse palatal shelves, early exposure of excessive RA induced Wnt signaling and Wnt-related gene expression in E11.5/E12.5 mouse embryonic frontonasal/maxillary processes. A conserved regulatory network of miR-484-Fzd5 was identified to play critical roles in RA-regulated craniofacial development using RNA-seq. In addition, subsequent osteogenic/chondrogenic differentiation were differentially regulated in discrete mouse embryonic facial prominences in response to early RA induction, demonstrated using both in vitro and in vivo analyses.