Nr2f1a balances atrial chamber and atrioventricular canal size via BMP signaling-independent and -dependent mechanisms

Developmental biology

Jacob T. Gafranek^2,3¹  Ariel B. Rydeen^2,3²  Padmapriyadarshini Ravisankar^3³  Tiffany B. Duong^1,3⁴  Yuntao Charlie Song^2,3⁵ 

[1] Developmental Biology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States^4;Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, United States^5;Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States^2;Molecular and Developmental Biology Master's Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States^1;The Heart Institute and Molecular Cardiovascular Biology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States^3

关键词: Nr2f1a;    Zebrafish;    Atrial myocardium;    Atrioventricular canal;    Valve development;    Cardiac chambers;   

DOI  :  10.1016/j.ydbio.2017.11.010

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

Determination of appropriate chamber size is critical for normal vertebrate heart development. Although Nr2f transcription factors promote atrial maintenance and differentiation, how they determine atrial size remains unclear. Here, we demonstrate that zebrafish Nr2f1a is expressed in differentiating atrial cardiomyocytes. Zebrafish nr2f1a mutants have smaller atria due to a specific reduction in atrial cardiomyocyte (AC) number, suggesting it has similar requirements to Nr2f2 in mammals. Furthermore, the smaller atria in nr2f1a mutants are derived from distinct mechanisms that perturb AC differentiation at the chamber poles. At the venous pole, Nr2f1a enhances the rate of AC differentiation. Nr2f1a also establishes the atrial-atrioventricular canal (AVC) border through promoting the differentiation of mature ACs. Without Nr2f1a, AVC markers are expanded into the atrium, resulting in enlarged endocardial cushions (ECs). Inhibition of Bmp signaling can restore EC development, but not AC number, suggesting that Nr2f1a concomitantly coordinates atrial and AVC size through both Bmp-dependent and independent mechanisms. These findings provide insight into conserved functions of Nr2f proteins and the etiology of atrioventricular septal defects (AVSDs) associated with NR2F2 mutations in humans.

【 授权许可】

CC BY