Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system
Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system
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DOI：
10.1016/j.ydbio.2004.10.025
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发表时间：
2005-02-15
影响因子：
2.7
通讯作者：
Johnson, RL
中科院分区：
文献类型：
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作者：
Kokubo, H;Miyagawa-Tomita, S;Johnson, RL
Notch信号在心血管发育的多个方面都是必需的，包括动-静脉分化、分离和缓冲形成。尽管认识到Notch通路在正常心血管发育中的重要性，但其直接下游效应尚不清楚。可能的候选效应物是bHLH转录因子家族的毛状和分裂相关增强子（hesr）的成员。然而，个体hesr基因的突变分析迄今未能阐明其在所有notch介导的心血管信号事件中的作用。gridlock突变体就是一个很明显的例子。gridlock突变体是斑马鱼中与小鼠hesr2对应的基因，具有血管缺陷，而小鼠hesr2突变体只有心脏缺陷。对这些差异的一种可能解释是她的家庭成员之间的功能冗余。在这里，我们报告了缺乏hesr1基因的小鼠是可存活和可生育的，而hesr1和hesr2基因敲除的小鼠在性交后11.5天（dpc）是胚胎致死的，并且再现了大多数已知的Notch通路突变体的心血管表型，包括动脉-静脉规范、分隔和缓冲形成的缺陷。综上所述，我们的研究结果表明，在发育中的心脏和血管系统中，hesr1和hesr2介导Notch信号通路是必需的。(C) 2004爱思唯尔公司版权所有。
Notch signaling is required for multiple aspects of cardiovascular development, including arterial-venous differentiation, septation and cushion formation. Despite recognition of the importance of the Notch pathway in normal cardiovascular development, the proximate downstream effectors are not yet known. Likely candidate effectors are members of the hairy and enhancer of split related (hesr) family of bHLH transcription factors. However, mutational analysis of individual hesr genes has so far failed to elucidate their role in all Notch-mediated cardiovascular signaling events. An example of this is evident for mutants of gridlock, the zebrafish counterpart of mouse hesr2, which have vascular defects, whereas mouse hesr2 mutants have only cardiac defects. One possible explanation for these differences could be functional redundancy between hesr family members. Here, we report that mice lacking the hesr1 gene are viable and fertile, whereas knockout mouse of both hesr1 and hesr2 is embryonic lethal at 11.5 days postcoitum (dpc) and recapitulates most of the known cardiovascular phenotypes of disrupted Notch pathway mutants including defects in arterial-venous specification, septation and cushion formation. Taken together, our results demonstrate a requirement for hesr1 and hesr2 in mediating Notch signaling in the developing cardiac and vascular systems. (C) 2004 Elsevier Inc. All rights reserved.