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Function analysis of Notch signaling in cardiogenesis

Notch信号在心脏发生中的功能分析

基本信息

批准号：
15591139
负责人：
MIYAGAWA Sachiko
金额：
$ 2.43万
依托单位：
Tokyo Women's Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591139/
关键词：
Notch signaling hesr gene heart morphogenesis development mouse

项目摘要

Notch signaling is an evolutionary conserved mechanism for cell fate specification and embryonic development in organisms ranging from flies to human. Notch encodes a transmembrane receptor with extracellular epithelial growth factor-like repeats and a short intracellular domain. In vertebrates, Notch signaling is required for normal neurogenesis, fate choices in the inner ear, somitogenesis, myogenesis, limb bud development, left-right asymmetry, lymphoid cell development, and kidney development. Recently a variety of evidence suggests that Notch signaling has an important role during cardiovascular development.One set of direct transcriptional targets of the Notch signaling pathway in Drosophila and vertebrates is the hairy and enhancer of split-type basic helix-loop-helix genes. We described previously a novel related gene that we called hairy and enhancer of split-related(hesr) gene. Hesr gene products have been reported to be transcriptional repressors of the Notch signaling pathw … More ay. A targeted mutant mice in hesr1 or hesr3 gene have no altered phenotype, however, Aesr2-knockout mice revealed cardiac anomalies. We confirmed the anomalies using echocardiographic analysis, and anatomical, histological, and transmission electro-micrographic findings. The mutant mice showed tricuspid and mitral valve regurgitation, and dysplasia of the atrio-ventricular(AV) valves, a perimembranous ventricular septal defect, a secundum atrial septal defect. These results suggest that hesr2 plays an important role in the formation and function of the AV valves. In addition, hesr2 activity may be important for proper development of cardiomyocytes.We generated mouse embryos lacking both hesr1 and hesr2. They were embryonic lethal due to severe cardiovascular malformation at 11.5 days postcoitum(dpc). Hesr1/2 double mutants had a single large ventricle, indicating that ventricular septum formation is blocked. At 9.5 dpc the mutant hearts had the compact and trabecular zones in the ventricle, however, the ventricle at 10.5 dpc showed poor trabecular formation due to apoptosis. In addition, few cells underwent endocardial to mesenchymal trasformation in the developing AV cushions. These results demonstrate hesr1 and hesr2 as mediators of Notch signaling are required for the developing heart. Less

Notch信号是从果蝇到人类的生物体中细胞命运指定和胚胎发育的进化保守机制。Notch编码具有细胞外上皮生长因子样重复序列和短的细胞内结构域的跨膜受体。在脊椎动物中，Notch信号传导是正常神经发生、内耳命运选择、体节发生、肌发生、肢芽发育、左右不对称、淋巴细胞发育和肾脏发育所必需的。近年来，多种证据表明Notch信号在心血管发育过程中发挥重要作用，其中一组Notch信号通路在果蝇和脊椎动物中的直接转录靶点是分裂型碱性螺旋-环-螺旋基因的毛状和增强子。我们以前描述了一个新的相关基因，我们称之为hairy和分裂相关增强子（hesr）基因。Hesr基因产物是Notch信号通路的转录抑制因子， ...更多信息嗯。hesr 1或hesr 3基因的靶向突变小鼠没有改变表型，然而，Aesr 2基因敲除小鼠显示心脏异常。我们通过超声心动图分析、解剖学、组织学和透射电镜检查结果证实了这些异常。突变小鼠表现出三尖瓣和二尖瓣反流，房室（AV）瓣膜发育不良，膜周室间隔缺损，继发性房间隔缺损。这些结果表明hesr 2在房室瓣的形成和功能中起重要作用。此外，hesr 2的活性可能对心肌细胞的正常发育很重要，我们培育了同时缺乏hesr 1和hesr 2的小鼠胚胎。它们在胚胎发育后11.5天（dpc）由于严重的心血管畸形而死亡。Hesr 1/2双突变体具有单个大心室，表明室间隔形成受阻。在9.5 dpc时，突变心脏的心室中具有致密区和小梁区，然而，在10.5 dpc时，由于细胞凋亡，心室显示出较差的小梁形成。此外，在发育中的AV垫中，很少有细胞经历内皮细胞向间充质转化。这些结果表明，hesr 1和hesr 2作为Notch信号传导的介质是发育中的心脏所必需的。少