Analysis for vasculogenesis using genetic engineering mice

Notch信号通路通过局部细胞间相互作用调节后生动物的细胞命运决定。Notch信号传导影响细胞增殖、分化，并且是从苍蝇到人类的进化上保守的调节系统。它的功能障碍导致了各种各样的发育缺陷和成人病理。我们研究了分裂相关（hesr）基因，编码基本螺旋-环-螺旋转录抑制因子，这是下游目标的Notch信号。虽然斑马鱼的gridlock突变体，小鼠hesr 2的同源物，导致动脉成熟缺陷，hesr 2敲除小鼠失去动脉成熟缺陷。相反，我们发现小鼠心脏形态异常，房室瓣发育不良，室间隔缺损，并使用经胸超声心动图5天大的纯合子小鼠继发性房间隔缺损。hesr 1和hesr 2双基因敲除小鼠显示出血管异常，这与斑马鱼的交通堵塞突变体惊人地相似。Hesr 1和Hesr 2在房室瓣形成期间的上皮-间充质转化和心室中小梁细胞的维持以及血管的动静脉分化中协同起作用。

Notch signaling pathway regulates cell-fate decisions in metazoans through local cell-cell interactions. Notch signaling influences cell proliferation, differentiation, and is an evolutionarily conserved regulation system ranging from flies to humans. Its dysfunction has resulted in a tremendous variety of developmental defects and adult pathologies. We examined the hairy and enhancer of split-related (hesr) genes, encoding basic helix-loop-helix transcription suppressor factors, which are downstream targets of Notch signaling. Although zebrafish mutants of gridlock, a homolog of mouse hesr2, leads to arterial maturation defects, hesr2 knockout mice lost arterial maturation defects. Instead of that, we showed that the mice had anomalies of cardiac morphology, dysplasia of the atrioventricular valve, a ventricular septal defect, and a secundum atrial septal defect using transthoracic echocardiography on 5-day-old homozygous mice. Double knockout mice for hesr1 and hesr2 showed vascular anomalies that are strikingly similar to that of the zebrafish gridlock mutants. Hesr1 and hesr2 function synergistically in epithelial- mesenchymal transformation during atrioventricular valve formation and maintenance of trabecular cells in the ventricles, and in arterial-venous differentiation of blood vessels.