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

Nanchao Hong,Huilin Xie,Erge Zhang,Bin Zhou,Alex F Chen,Sun Chen,Qi Zhang,Yongguo Yu,Yu Yu,Kun Sun,Lihui Jin,Yanan Lu

doi:10.1038/s41419-021-03658-z

Abstract

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.

Highlights

Congenital heart defects (CHDs) are the most common form of birth defects, account for ~1% of newborns, and are the leading cause of infant death resulting from birth abnormality, with 22.5% deaths of infants[1]
A key process in atrioventricular septal development is the endothelial to mesenchymal transition (EndMT), which consists of multiple cellular events including the delamination of endocardial cells from the atrioventricular canal (AVC) endocardium, the acquisition of mesenchymal phenotypes and their invasion into the extracellular matrix (ECM)[7,8,9]
Based on the criteria mentioned in the section “Materials and methods”, we identified 10 rare copy number variants (CNVs) in 13 patients with atrioventricular septal defect (AVSD) (Supplementary Table S1)

Summary

Introduction

Congenital heart defects (CHDs) are the most common form of birth defects, account for ~1% of newborns, and are the leading cause of infant death resulting from birth abnormality, with 22.5% deaths of infants[1]. Atrioventricular septal defect (AVSD) covers a spectrum of heart anomalies with a common atrioventricular connection and has an incidence of 4–5.3 per 10,000 live birth[4,5,6]. A key process in atrioventricular septal development is the endothelial to mesenchymal transition (EndMT), which consists of multiple cellular events including the delamination of endocardial cells from the atrioventricular canal (AVC) endocardium, the acquisition of mesenchymal phenotypes and their invasion into the extracellular matrix (ECM)[7,8,9]. The underlying genetic etiology of AVSD still remains poorly understood

Methods

Results

Conclusion