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Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor  Sox7  has critical functions in the vascular development and angiogenesis. It is unclear whether  Sox7  also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with  Sox7  haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple  Sox7  conditional loss-of-function mice models were generated to explore the role of  Sox7  in atrioventricular cushion development.  Sox7  deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in  Sox7  deficiency atrioventricular cushions. Mechanistically,  Sox7  deficiency reduced the expressions of  Bmp2  in atrioventricular canal myocardium and  Wnt4  in endocardium, and  Sox7  binds to  Wnt4  and  Bmp2  directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by  Sox7  deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify  Sox7  as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4–Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects.

The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling