Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status
Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status
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DOI：
10.1523/jneurosci.21-17-06687.2001
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发表时间：
2001-09-01
影响因子：
5.3
通讯作者：
McKinnon, PJ
中科院分区：
文献类型：
--
作者：
Lee, Y;Chong, MJ;McKinnon, PJ
共济失调-毛细血管扩张症（Ataxia-telangiectasia，A-T）是由共济失调毛细血管扩张症突变（ataxia telangiectasia mutated）引起的神经退行性疾病。ATM在神经系统中功能的分子细节尚不清楚，尽管A-T中的神经病变可能是发育性的，因为它们出现在儿童时期。ATM基因敲除小鼠的神经系统表现出明显的DNA损伤诱导的细胞凋亡缺陷，这表明ATM可能具有消除DNA损伤神经元的功能。在这里，我们表明，ATM依赖性细胞凋亡发生在神经发生的离散阶段。γ射线照射的小鼠胚胎的分析表明，Atm依赖性细胞凋亡只发生在有丝分裂后的人口中存在的神经上皮脑室下区的发展中的神经系统。值得注意的是，Atm缺乏并不能阻止放射诱导的多能前体细胞凋亡，这些细胞位于增殖的心室区。ATM依赖性凋亡需要p53，并与p53的特异性磷酸化和caspase-3激活相一致。因此，这些数据表明，Atm的功能在神经发生的早期，并强调Atm在消除受损的有丝分裂后的神经细胞的选择性要求。此外，这些数据表明，神经细胞的分化状态是激活某些凋亡途径的关键决定因素。
Ataxia-telangiectasia (A-T) is a neurodegenerative syndrome resulting from dysfunction of ATM (ataxia telangiectasia mutated). The molecular details of ATM function in the nervous system are unclear, although the neurological lesions in A-T are probably developmental because they appear during childhood. The nervous systems of Atm-null mice show a pronounced defect in apoptosis that is induced by DNA damage, suggesting that ATM may function to eliminate DNA-damaged neurons. Here we show that Atm-dependent apoptosis occurs at discrete stages of neurogenesis. Analysis of gamma -irradiated mouse embryos showed that Atm-dependent apoptosis occurred only in the postmitotic populations that were present in the neuroepithelial subventricular zone of the developing nervous system. Notably, Atm deficiency did not prevent radiation-induced apoptosis in multipotent precursor cells residing in the proliferating ventricular zone. Atm-dependent apoptosis required p53 and coincided with the specific phosphorylation of p53 and caspase-3 activation. Thus, these data show that Atm functions early in neurogenesis and underscore the selective requirement for Atm in eliminating damaged postmitotic neural cells. Furthermore, these data demonstrate that the differentiation status of neural cells is a critical determinant in the activation of certain apoptotic pathways.