Abstract
Runx1 deficiency results in an anteriorly specific cleft palate at the boundary between the primary and secondary palates and in the first rugae area of the secondary palate in mice. However, the cellular and molecular pathogenesis underlying such regional specificity remain unknown. In this study, Runx1 epithelial-specific deletion led to the failed disintegration of the contacting palatal epithelium and markedly downregulated Tgfb3 expression in the primary palate and nasal septum. In culture, TGFB3 protein rescued the clefting of the mutant. Furthermore, Stat3 phosphorylation was disturbed in the corresponding cleft regions in Runx1 mutants. The Stat3 function was manifested by palatal fusion defects in culture following Stat3 inhibitor treatment with significant downregulation of Tgfb3. Tgfb3 is therefore a critical target of Runx1 signaling, and this signaling axis could be mediated by Stat3 activation. Interestingly, the expression of Socs3, an inhibitor of Stat3, was specific in the primary palate and upregulated by Runx1 deficiency. Thus, the involvement of Socs3 in Runx1-Tgfb3 signaling might explain, at least in part, the anteriorly specific downregulation of Tgfb3 expression and Stat3 activity in Runx1 mutants. This is the first study to show that the novel Runx1-Stat3-Tgfb3 axis is essential in anterior palatogenesis.
Highlights
Cleft palate (CP) represents one of the major congenital craniofacial birth defects[1,2]
In this study, using epithelial-specific Runx[1] deletion mice, we demonstrate that Tgfb[3] is an essential target of Runx[1] signaling in anterior-specific disintegration of the fusing palatal epithelium and that the site-specific downregulation of Stat[3] phosphorylation plays a central role in downregulating the Tgfb[3] expression and manifesting palatal clefting upon Runx[1] loss
We demonstrate that signal transducer and activator of transcription 3 (Stat3)-mediating Runx1-Tgfb[3] axis is a novel regulatory pathway that regulates the palatal fusion in the anterior regions
Summary
Cleft palate (CP) represents one of the major congenital craniofacial birth defects[1,2]. Some transcription factors and signaling molecules, such as Msx[1], Bmp[4], Shh, Fgf[10], Fgf[7], and Shox[2] are recognized as anterior-specific[14,15] Spatial distribution of such genes within the palate, together with the palatal phenotypes in their null mutant, clearly highlights the importance of regionally specific regulatory mechanism at the molecular level. In this study, using epithelial-specific Runx[1] deletion mice, we demonstrate that Tgfb[3] is an essential target of Runx[1] signaling in anterior-specific disintegration of the fusing palatal epithelium and that the site-specific downregulation of Stat[3] phosphorylation plays a central role in downregulating the Tgfb[3] expression and manifesting palatal clefting upon Runx[1] loss. We demonstrate that Stat3-mediating Runx1-Tgfb[3] axis is a novel regulatory pathway that regulates the palatal fusion in the anterior regions
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