Abstract
ABSTRACTCore binding factor β (Cbfb) is a cofactor of the Runx family of transcription factors. Among these transcription factors, Runx1 is a prerequisite for anterior-specific palatal fusion. It was previously unclear, however, whether Cbfb served as a modulator or as an obligatory factor in the Runx signaling process that regulates palatogenesis. Here, we report that Cbfb is essential and indispensable in mouse anterior palatogenesis. Palatal fusion in Cbfb mutants is disrupted owing to failed disintegration of the fusing epithelium specifically at the anterior portion, as observed in Runx1 mutants. In these mutants, expression of TGFB3 is disrupted in the area of failed palatal fusion, in which phosphorylation of Stat3 is also affected. TGFB3 protein has been shown to rescue palatal fusion in vitro. TGFB3 also activated Stat3 phosphorylation. Strikingly, the anterior cleft palate in Cbfb mutants is further rescued by pharmaceutical application of folic acid, which activates suppressed Stat3 phosphorylation and Tgfb3 expression in vitro. With these findings, we provide the first evidence that Cbfb is a prerequisite for anterior palatogenesis and acts as an obligatory cofactor in the Runx1/Cbfb-Stat3-Tgfb3 signaling axis. Furthermore, the rescue of the mutant cleft palate using folic acid might highlight potential therapeutic targets aimed at Stat3 modification for the prevention and pharmaceutical intervention of cleft palate.
Highlights
Cleft palate is the most common congenital anomalies in humans, and its etiology is complex (Dixon et al, 2011; Murray, 2002)
Summary Statement Epithelial deletion of Cbfb results in an anterior cleft palate with impaired fusion of the palatal process and folic acid application rescues the mutant phenotype with Stat3 activation in vitro
Palatal fusion in Cbfb mutants is disturbed due to failed disintegration of the fusing epithelium at the anterior portion, as is observed in Runx1 mutants
Summary
Cleft palate is the most common congenital anomalies in humans, and its etiology is complex (Dixon et al, 2011; Murray, 2002). Epithelial-specific loss of Runx results in failure of palatal fusion at the anterior portion between the primary and the secondary palate with failed disintegration of the medial-edge epithelium In this mutants, the expression of Tgfb, a critical regulator of the palatal fusion, was disturbed among various molecules regulating palatogenesis, and TGFB3 protein rescues the mutant cleft palate, Tgfb is critical in Runx signaling in palatogenesis (Sarper et al, 2018). The expression of Tgfb, a critical regulator of the palatal fusion, was disturbed among various molecules regulating palatogenesis, and TGFB3 protein rescues the mutant cleft palate, Tgfb is critical in Runx signaling in palatogenesis (Sarper et al, 2018) In this Runx mutants, Stat phosphorylation was downregulated at the anterior palate, and Stat inhibitor disturbed the anterior palatal fusion accompanied by the downregulation on the Tgfb expression in vitro, indicating that Runx1-Tgfb signaling axis was mediated by Stat phosphorylation (Sarper et al, 2018). These findings suggested that extrinsic modification of the Stat activity affects Tgfb signaling and may be a potential therapeutic target in pharmaceutical intervention for cleft palate (Sarper et al, 2018)
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