Analysis for vasculogenesis using genetic engineering mice

Notch信号通路通过细胞与细胞的局部相互作用调节后生动物细胞命运的决定。Noch信号影响细胞的增殖和分化，是一种从苍蝇到人类的进化保守的调节系统。它的功能障碍已经导致了各种各样的发育缺陷和成人病理。我们研究了裂解相关基因的毛发和增强子，编码基本的螺旋-环-螺旋转录抑制因子，这是Notch信号的下游目标。虽然斑马鱼GRDLOCK的突变会导致动脉成熟缺陷，但是HESR2基因敲除的小鼠会丢失动脉成熟缺陷。取而代之的是，我们在5天大的纯合子小鼠上用经胸超声心动图显示小鼠心脏形态异常，房室瓣发育不良，室间隔缺损和第二孔房间隔缺损。Hesr1和Hesr2的双基因敲除小鼠表现出与斑马鱼堵塞突变惊人地相似的血管异常。Hesr1和Hesr2在房室瓣膜形成和维持脑室小梁细胞的上皮间充质转化以及血管的动静脉分化中起协同作用。

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.