Retinoic acid alters the proliferation and survival of the epithelium and mesenchyme and suppresses Wnt/β-catenin signaling in developing cleft palate

Abstract

Retinoic acid (RA) contributes to cleft palate; however, the cellular and molecular mechanisms responsible for the deleterious effects on the developing palate are unclear. Wnt signaling is a candidate pathway in the cleft palate and is associated with RA in organ development; thus, we aim to investigate whether RA-induced cleft palate also results from altered Wnt signaling. Administration of RA to mice altered cell proliferation and apoptosis in craniofacial tissues by regulating molecules controlling cell cycle and p38 MAPK signaling, respectively. This altered cell fate by RA is a crucial mechanism contributing to 100% incidence of cleft palate. Moreover, Wnt/β-catenin signaling was completely inhibited by RA in the early developing palate via its binding and activation with RA receptor (RAR) and is responsible for RA-induced cleft palate. Furthermore, PI3K/Akt signaling was also involved in actions of RA. Our findings help in elucidating the mechanisms of RA-induced cleft palate.

Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

“…atRA has been proposed as a model agent not only for the inhibition of palate elevation but also retention of the MEE [4]. The TGF and Wnt signaling pathways have been implicated in atRA-induced inhibition of palate elevation [16,17]. However, few studies have examined the mechanism underlying MEE retention induced by atRA.…”

“…Due to different dosages, atRA can not only promote, but also inhibit, the proliferation of cells [18]. It has been reported that atRA treatment may inhibit the proliferation of glioma cells [19] and mouse embryonic palatal mesenchymal cells [16,17]. atRA-induced proliferation and survival has also been assessed in lung cancer cells [20,21], chicken primordial germ cells and neuronal cells [22].…”

Implications of the Wnt5a/CaMKII Pathway in Retinoic Acid-Induced Myogenic Tongue Abnormalities of Developing Mice

“…Early movement of mouse tongue is adapted to functional activities such as suckling, swallowing, and chewing1. Prenatal exposure to excess RA triggers cleft palate formation in mouse fetuses91920, while the malformation of tongue was rarely reported2122. The aberrant morphogenesis of tongue and underlying molecular and cellular mechanisms that regulate tongue development in the presence of excess RA in fetal mice remain unclear.…”

A functional polymorphism in the pre-miR-146a gene is associated with the risk of nonsyndromic orofacial cleft

“…Normal cell‐cycle progression and proliferation of palatal mesenchymal cells are important for palatal development (Hu, Gao, Liao, Tang, & Lu, ; Li et al., ). Disturbance of either of these processes can cause cleft palate (Tian et al., ).…”