Analysis of the Notch-HES pathway that regulates mammalian neurogenesis

调节哺乳动物神经发生的Notch-HES通路分析

• 批准号: 09670009
• 负责人: ISHIBASHI Makoto
• 金额: $ 2.37万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670009/
• 关键词: Neural precursor cell; Differentiation; Transcriptional regulation; Myogenesis; HES; Notch; Gene targeting; 神経分化; 脳; 網膜; マウス胎児; ノックアウトマウス

In order to elucidate the transcriptional regulation of mammalian neurogenesis, we analyzed the roles HES-1, which is a mammalian homolog of Drosophila hairy and Enhancer of split genes, in neurogenesis and obtained the following results.1. HES-l was intensely expressed in immature tissues of rodent embryos, including neural and muscular tissues, and the expression level declined along with tissue differentiation.2. HES- 1 suppressed the differentiation of cultured myogenic cells which is mediated by Myo-D.3. When HES-l was induced in neural precursor cells in the central nervous system of mouse embryos, it completely inhibited neuronal differentiation.4. In mice lacking HES-1, the expression of Mashl increased and premature neurogenesis occurred. These mice had cranial neural tube defects resulting from the failure of neural tube closure.5. When the retinal tissue of fetal mice lacking HES-l was cultured in vitro, the neural retina showed premature and abnormal differentiation.6. From an in vitro promotor analysis of mouse HES-1 gene, it was revealed that HES-1 expression is regulated by itself (negative autoregulation).From these observations, it was concluded that HES-I negatively regulates mammalian neurogenesis.

为了阐明哺乳动物神经发生的转录调控机制，我们分析了果蝇毛状基因和分裂增强子基因的哺乳动物同源基因HES-1在神经发生中的作用，得到以下结果. HES-1在啮齿类动物胚胎的未成熟组织中有较强的表达，包括神经组织和肌肉组织，表达水平沿着而下降. HES- 1可抑制Myo-D介导的成肌细胞分化。当在小鼠胚胎中枢神经系统的神经前体细胞中诱导HES-I时，它完全抑制神经元的分化.在缺乏HES-1的小鼠中，Mashl的表达增加，并发生过早的神经发生。这些小鼠具有由于神经管闭合失败而导致的颅神经管缺陷。缺乏HES-1的胎鼠视网膜组织在体外培养时，神经视网膜出现过早分化和异常分化.通过对小鼠HES-1基因启动子的体外分析，发现HES-1基因的表达是受自身调控的（负性自身调节），从而得出结论：HES-1负性调节哺乳动物神经发生。

项目成果

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Makoto Ishibashi 等：“小鼠 Hes2 基因的结构、染色体位点和启动子，果蝇毛状和分裂增强子的同源物。”49. 69-75 (1998)。

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Kenji Mizuseki 等人：“SoxD：非洲爪蟾胚胎中前神经组织诱导的重要介质”21·1（1998）。

Ishibashi, M.et al.: "bHLH transcription factors and mammalian neuronal differentiation." International Journal of Biochemistry and Cell Biology.29. 1389-1399 (1998)

Ishibashi, M.等人：“bHLH 转录因子和哺乳动物神经元分化。”