Anterior cleft palate due to Cbfb deficiency and its rescue by folic acid
Anterior cleft palate due to Cbfb deficiency and its rescue by folic acid
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DOI：
10.1242/dmm.038851
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发表时间：
2019-06-01
影响因子：
4.3
通讯作者：
Yamashiro, Takashi
中科院分区：
文献类型：
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作者：
Sarper, Safiye E.;Inubushi, Toshihiro;Yamashiro, Takashi
核心结合因子β(Cbfb)是RUNX转录因子家族的辅因子。在这些转录因子中，Runx1是前部特异的腭部融合的先决条件。然而，之前还不清楚Cbfb在调节腭裂发生的RUNX信号过程中是作为一个调节器还是作为一个强制性因素。在这里，我们报告Cbfb在小鼠前腭裂发生中是必不可少的和不可或缺的。正如在Runx1突变体中观察到的那样，Cbfb突变体中的腭部融合被破坏，这是由于融合上皮未能解体，特别是在Runx1突变体中。在这些突变体中，TGFB3在腭裂融合失败区的表达受到干扰，其中STAT3的磷酸化也受到影响。TGFB3蛋白已被证明在体外挽救了腭裂融合。TGFB3还激活了STAT3的磷酸化。值得注意的是，Cbfb突变体的前腭裂可以通过药物应用叶酸来进一步挽救，叶酸在体外激活了被抑制的STAT3磷酸化和TGFB3的表达。通过这些发现，我们提供了第一个证据，证明Cbfb是前腭裂发生的先决条件，并在RUNX1/Cbfb-STAT3-TGFB3信号轴中扮演着必需的辅助因子的角色。此外，使用叶酸挽救突变型腭裂可能突出针对STAT3修饰的潜在治疗靶点，用于预防和药物干预腭裂。
Core binding factor beta (Cbfb) is a cofactor of the Runx family of transcription factors. Among these transcription factors, Runxl 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 Runxl 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.