Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
PLoS Genet. 2019 Feb 5;15(2):e1007962. doi: 10.1371/journal.pgen.1007962. eCollection 2019 Feb.
Multiple syndromes share congenital heart and craniofacial muscle defects, indicating there is an intimate relationship between the adjacent cardiac and pharyngeal muscle (PM) progenitor fields. However, mechanisms that direct antagonistic lineage decisions of the cardiac and PM progenitors within the anterior mesoderm of vertebrates are not understood. Here, we identify that retinoic acid (RA) signaling directly promotes the expression of the transcription factor Nr2f1a within the anterior lateral plate mesoderm. Using zebrafish nr2f1a and nr2f2 mutants, we find that Nr2f1a and Nr2f2 have redundant requirements restricting ventricular cardiomyocyte (CM) number and promoting development of the posterior PMs. Cre-mediated genetic lineage tracing in nr2f1a; nr2f2 double mutants reveals that tcf21+ progenitor cells, which can give rise to ventricular CMs and PM, more frequently become ventricular CMs potentially at the expense of posterior PMs in nr2f1a; nr2f2 mutants. Our studies reveal insights into the molecular etiology that may underlie developmental syndromes that share heart, neck and facial defects as well as the phenotypic variability of congenital heart defects associated with NR2F mutations in humans.
多种综合征具有先天性心脏和颅面肌肉缺陷，表明心脏和咽肌（PM）前体细胞场之间存在密切关系。然而，脊椎动物前中胚层中直接指导心脏和 PM 前体细胞拮抗谱系决定的机制尚不清楚。在这里，我们发现视黄酸（RA）信号直接促进了转录因子 Nr2f1a 在前侧板中胚层中的表达。利用斑马鱼 nr2f1a 和 nr2f2 突变体，我们发现 Nr2f1a 和 Nr2f2 具有冗余的需求，限制了心室心肌细胞（CM）的数量并促进了后 PM 的发育。在 nr2f1a; nr2f2 双突变体中 Cre 介导的遗传谱系追踪显示，tcf21+祖细胞可产生心室 CM 和 PM，在 nr2f1a; nr2f2 突变体中，更频繁地成为心室 CM，可能以牺牲后 PM 为代价。我们的研究揭示了分子病因学的见解，这些病因学可能是导致具有心脏、颈部和面部缺陷以及与 NR2F 基因突变相关的先天性心脏缺陷的表型变异性的原因。
