Identification of the dysregulated let-7c-Sox2 network in the facial prominences of mouse embryos with early retinoid acid exposure

Abstract

RA signaling is crucial for the anteroposterior pattern formation during neural crest induction and acts as a key environmental cue for cranial neural crest cell migration as well as the subsequent mesenchymal proliferation and differentiation. Congenital malformations including cleft lip and palate have been shown associated with altered embryonic RA signaling both in human and in animal models. In this study, a dysregulated let-7c-Sox2 network was identified in the altered transcriptomic profiles of the facial prominences of E12.5 mouse embryos induced by early RA exposure. Ubiquitously increased expression of let-7c was observed in the epithelium and the mesenchyme of facial prominences of the RA treated mouse and chick embryos. Direct binding and regulation between let-7c and Sox2 was verified using luciferase assay and significant negative correlation between let-7c and Sox2 expression was observed in vitro. Reduced Sox2 expression was predominantly identified in the epithelium of maxillary and palate shelves from E10.5 to E12.5 in RA-induced mouse embryos, resulted in oral adhesion and hypoplasia of palatal shelves that could partly be explained by the reduced mesenchymal proliferation due to upregulation of let-7c, as shown by the results of cell proliferation assay in vitro.