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bioRxiv · 10.1101/2020.12.04.412288

SOX7 deficiency causes ventricular sepal defects through its effects on endocardial-to-mesenchymal transition and the expression of Wnt4 and Bmp2

Hernandez-Garcia, A.·Kim, S.·Li, Y.·Kim, B. J.·Zaveri, H. P.·Jordan, V. K.·Ljungberg, M. C.·Chen, R.·Lanz, R. B.·Scott, D. A.
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Abstract

SOX7 is located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with septal defects. Sox7-/- embryos die of heart failure around E11.5 due to defects in vascular remodeling. These embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. We also observed a ventricular septal defect in a rare Sox7flox/-;Tie2-Cre embryo that escaped early lethality. This led us to hypothesize that SOX7 plays a critical developmental role in the endocardium of the atrioventricular (AV) canal. We subsequently used AV explant studies to show that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). Since SOX7 is a transcription factor, we hypothesized that it functions in the endocardium by regulating the expression of EndMT-related genes. To identify these genes in an unbiased manner, we performed RNA-seq on pooled E9.5 hearts tubes harvested from Sox7-/- embryos and their wild-type littermates. We found that Wnt4 transcript levels were severely reduced, which we confirmed by RNA in situ hybridization. Previous studies have shown that WNT4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of BMP2 in the myocardium. Consistent with these findings, we found that Bmp2 transcript levels were diminished in Sox7-/- embryonic hearts. We conclude that SOX7 promotes EndMT in the developing AV canal by modulating the expression of Wnt4 and Bmp2. These data also provide additional evidence that haploinsufficiency of SOX7 contributes to the congenital heart defects seen in individuals with recurrent 8p23.1 microdeletions. SUMMARY STATEMENTIn the developing atrioventricular canal, SOX7 promotes endocardial-to-mesenchymal transition (EndMT) by positively regulating Wnt4 and Bmp2 expression. SOX7 deficiency leads to the development of hypocellular endothelial cushions and ventricular septal defects.

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Hernandez-Garcia, A., Kim, S., Li, Y., Kim, B. J., Zaveri, H. P., Jordan, V. K., Ljungberg, M. C., Chen, R., Lanz, R. B., Scott, D. A.. 2020-12-05. SOX7 deficiency causes ventricular sepal defects through its effects on endocardial-to-mesenchymal transition and the expression of Wnt4 and Bmp2. https://doi.org/10.1101/2020.12.04.412288

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