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.
Highlights
Palatal shelves, composed of a core of mesenchyme covered by an epithelium, grow vertically on both sides of the tongue from embryonic day 13.5 (E13.5) in the mouse
Retinoic acid (RA) totally changed the morphogenesis of craniofacial tissues in at least three aspects: (1) palatal shelves abnormally retained the capability of vertical growth from E13.5 to E15.5; (2) anterior palatal shelves lost the grooves between the palatal shelf and the body of maxilla at E13.5 and E14.5, which might obstruct the elevation of palatal shelves; and (3) the action of tongue withdrawal could not prepare enough space for elevation of palatal shelves
Cell proliferation appeared in all craniofacial tissues, including the epithelium and mesenchyme, for a hyperproliferative situation in early embryo development but gradual reduction from E13.5 to E15.5
Summary
Palatal shelves, composed of a core of mesenchyme covered by an epithelium, grow vertically on both sides of the tongue from embryonic day 13.5 (E13.5) in the mouse. Retinoic acid (RA) has an essential role during embryonic development of regulating morphogenesis, cell proliferation and differentiation, and extracellular matrix production.[1,2,3] RA is widely used for skin diseases; excess exogenous RA can adversely affect craniofacial development in rodents and humans.[4,5] Cleft palate is one of the major malformations induced by RA in mouse fetuses. RA may have a direct effect on the fetus, disturb polysaccharide metabolism of the ground substance of the palatal processes, disturb the blood concentration of thyroid hormone and interfere with carbohydrate metabolism.[4,6] Notably in recent years, RA was linked to Wnt (wingless) signaling in organ development and disease therapy.[7,8,9] the mechanisms of action of RA in cleft palate formation are still not fully understood. We hypothesized that RA-induced cleft palate was associated with Wnt signaling by altering palatal cell fate in the crucial time of craniofacial development. We analyzed the protein expression of Wnt signaling molecules and investigated cell proliferation and survival after RA exposure from E13.5 to E15.5
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