The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling.
The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling.
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DOI：
10.1038/s41419-021-03658-z
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发表时间：
2021-04-12
影响因子：
9
通讯作者：
Sun K
中科院分区：
文献类型：
--
作者：
Hong N;Zhang E;Xie H;Jin L;Zhang Q;Lu Y;Chen AF;Yu Y;Zhou B;Chen S;Yu Y;Sun K
心脏间隔畸形在先天性心脏病中所占比例最大。转录因子Sox 7在血管发育和血管生成中具有重要作用。目前尚不清楚Sox 7是否也有助于心脏分隔的发展。我们通过对100例房室间隔缺损（AVSD）患者进行全外显子组测序，发现了一例伴有Sox 7单倍功能不全的8p23.1从头缺失。然后，建立多个Sox 7条件性功能丧失小鼠模型，以探讨Sox 7在房室垫发育中的作用。Sox 7缺陷小鼠胚胎表现出部分AVSD和受损的内皮间质转化（EndMT）。转录组分析显示，BMP信号通路在Sox 7缺陷的房室垫中显著下调。Sox 7缺陷可降低房室管心肌中Bmp 2和内膜中Wnt 4的表达，Sox 7可直接与Wnt 4和Bmp 2结合。此外，WNT 4或BMP 2蛋白可以部分挽救由Sox 7缺陷引起的受损的EndMT过程，并且Noggin抑制BMP 2可以减弱WNT 4蛋白的作用。综上所述，我们的研究结果确定Sox 7作为一个新的AVSD致病候选基因，它可以通过Wnt 4-Bmp 2信号调节参与房室垫形态发生的EndMT。本研究为先天性心脏病的诊断和治疗提供了新的策略。
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.
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影响因子：
11.4
作者：
Pennington SM;Klutho PR;Xie L;Broadhurst K;Koval OM;McCormick ML;Spitz DR;Grumbach IM
通讯作者：
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