Dataset Information

NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.

ABSTRACT: Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development.First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NEXN inhibited cardiac contractile markers, serving as a negative regulator. Interestingly, we found this effect was mediated by GATA4, a crucial transcription factor that controls cardiac development by knockdown, overexpression, and rescue experiment, respectively. We then generated transgenic mouse models and surprisingly, we discovered cardiac-selective expression of the NEXN gene caused atrial septal defects (ASDs). Next, to search for the mutations in NEXN gene in patients suffering from ASDs, we sequenced the exon and exon-intron joint regions of the NEXN gene in 150 probands with isolated ASDs and identified three mutations in the conserved region of NEXN (c.-52-78C>A, K199E, and L227S), which were not found in 500 healthy controls. Finally, we characterize the related mechanisms and found all mutations inhibited GATA4 expression.We identify NEXN as a novel gene for ASD and its function to inhibit GATA4 established a critical regulation of an F-actin binding protein on a transcription factor in cardiac development.

SUBMITTER: Yang F

PROVIDER: S-EPMC4498134 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.

Yang Fan F Zhou Lei L Wang Qiguang Q You Xin X Li Ying Y Zhao Yong Y Han Xiaonan X Chang Zai Z He Xin X Cheng Chunyan C Wu Chong C Wang Wen-Jing WJ Hu Fang-Yuan FY Zhao Ting T Li Yang Y Zhao Ming M Zheng Gu-Yan GY Dong Jie J Fan Chun C Yang Juxian J Meng Xianmin X Zhang Youyi Y Zhu Xianyang X Xiong Jingwei J Tian Xiao-Li XL Cao Huiqing H

Cardiovascular research 20140527 2

<h4>Aims</h4>Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development.<h4>Methods and results</h4>First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NE ...[more]

PMID: 24866383

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Project description:Deletions of chromosome 1p36 are associated with a high incidence of congenital heart defects (CHDs). The arginine-glutamic acid dipeptide repeats gene (RERE) is located in a critical region for CHD on chromosome 1p36 and encodes a cardiac-expressed nuclear receptor co-regulator. Mutations affecting RERE cause atrial and ventricular septal defects (VSDs) in humans, and RERE-deficient mice also develop VSDs. During cardiac development, mesenchymal cells destined to form part of the atrioventricular (AV) septum are generated when endocardial cells in the AV canal undergo epithelial-to-mesenchymal transition (EMT) and migrate into the space between the endocardium and the myocardium. These newly generated mesenchymal cells then proliferate to fill the developing AV endocardial cushions. Here, we demonstrate that RERE-deficient mouse embryos have reduced numbers of mesenchymal cells in their AV endocardial cushions owing to decreased levels of EMT and mesenchymal cell proliferation. In the endocardium, RERE colocalizes with GATA4, a transcription factor required for normal levels of EMT and mesenchymal cell proliferation. Using a combination of in vivo and in vitro studies, we show that Rere and Gata4 interact genetically in the development of CHDs, RERE positively regulates transcription from the Gata4 promoter and GATA4 levels are reduced in the AV canals of RERE-deficient embryos. Tissue-specific ablation of Rere in the endocardium leads to hypocellularity of the AV endocardial cushions, defective EMT and VSDs, but does not result in decreased GATA4 expression. We conclude that RERE functions in the AV canal to positively regulate the expression of GATA4, and that deficiency of RERE leads to the development of VSDs through its effects on EMT and mesenchymal cell proliferation. However, the cell-autonomous role of RERE in promoting EMT in the endocardium must be mediated by its effects on the expression of proteins other than GATA4.This article has an associated First Person interview with the first author of the paper.

Dataset Information

NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.

Publications

NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.

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