Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
G3 (Bethesda). 2022 Jul 29;12(8). doi: 10.1093/g3journal/jkac155.
To discover genes implicated in human congenital disorders, we performed ENU mutagenesis in the mouse and screened for mutations affecting embryonic development. In this work, we report defects of heart development in mice homozygous for a mutation of coactivator-associated arginine methyltransferase 1 (Carm1). While Carm1 has been extensively studied, it has never been previously associated with a role in heart development. Phenotype analysis combining histology and microcomputed tomography imaging shows a range of cardiac defects. Most notably, many affected midgestation embryos appear to have cardiac rupture and hemorrhaging in the thorax. Mice that survive to late gestation show a variety of cardiac defects, including ventricular septal defects, double outlet right ventricle, and persistent truncus arteriosus. Transcriptome analyses of the mutant embryos by mRNA-seq reveal the perturbation of several genes involved in cardiac morphogenesis and muscle development and function. In addition, we observe the mislocalization of cardiac neural crest cells at E12.5 in the outflow tract. The cardiac phenotype of Carm1 mutant embryos is similar to that of Pax3 null mutants, and PAX3 is a putative target of CARM1. However, our analysis does not support the hypothesis that developmental defects in Carm1 mutant embryos are primarily due to a functional defect of PAX3.
为了发现与人类先天性疾病相关的基因，我们在小鼠中进行了ENU 诱变，并筛选影响胚胎发育的突变。在这项工作中，我们报告了共激活因子相关精氨酸甲基转移酶 1 (Carm1) 突变纯合子小鼠的心脏发育缺陷。虽然 Carm1 已经被广泛研究，但它以前从未与心脏发育的作用相关联。结合组织学和微计算机断层扫描成像的表型分析显示出一系列心脏缺陷。最值得注意的是，许多受影响的中期胚胎似乎有心脏破裂和胸腔出血。存活到晚期妊娠的小鼠表现出多种心脏缺陷，包括室间隔缺损、右心室双出口和永存动脉干。通过 mRNA-seq 对突变体胚胎的转录组分析揭示了几个涉及心脏形态发生和肌肉发育和功能的基因的扰动。此外，我们观察到心脏神经嵴细胞在 E12.5 时在流出道中的位置异常。Carm1 突变体胚胎的心脏表型与 Pax3 缺失突变体相似，而 PAX3 是 CARM1 的一个假定靶点。然而，我们的分析并不支持 Carm1 突变体胚胎的发育缺陷主要是由于 PAX3 的功能缺陷的假设。
