Ataxia telangiectasia mutated is essential during adult neurogenesis
Ataxia telangiectasia mutated is essential during adult neurogenesis
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DOI：
10.1101/gad.869001
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发表时间：
2001-03-01
影响因子：
10.5
通讯作者：
Barlow, C
中科院分区：
文献类型：
--
作者：
Allen, DR;van Praag, H;Barlow, C
共济失调性毛细血管扩张症（A-T）是一种常染色体隐性遗传疾病，其特征是正常的脑发育，随后进行性神经退行性变。在A-T（ATM）中突变的基因是涉及细胞周期调节和DNA修复的丝氨酸蛋白激酶。ATM在大脑中的作用及其丧失对神经元存活的后果仍不清楚。我们在体内和体外研究了ATM在成人神经前体细胞中的作用，以确定ATM缺陷（Atm（-/-））小鼠在生理背景下ATM在分裂和有丝分裂后神经细胞中的作用。我们证明，ATM是一个丰富的蛋白质在分裂的神经祖细胞，但显着下调细胞分化。在缺乏ATM的情况下，齿状回的神经祖细胞显示出异常高的增殖率和基因组不稳定性。在体内和细胞培养中，Atm（-/-）细胞对环境刺激的反应迟钝，环境刺激促进神经祖细胞增殖、存活和沿神经元谱系沿着分化。本研究定义了ATM在神经发生过程中的作用，证明了ATM是体外和体内正常细胞命运决定和神经元存活所必需的，并指出了进行性神经退行性疾病中神经元细胞丢失的机制。
Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by normal brain development followed by progressive neurodegeneration. The gene mutated in A-T (ATM) is a serine protein kinase implicated in cell cycle regulation and DNA repair. The role of ATM in the brain and the consequences of its loss on neuronal survival remain unclear. We studied the role of ATM in adult neural progenitor cells in vivo and in vitro to define the role of ATM in dividing and postmitotic neural cells from Atm-deficient (Atm(-/-)) mice in a physiologic context. We demonstrate that ATM is an abundant protein in dividing neural progenitor cells but is markedly down-regulated as cells differentiate. In the absence of ATM, neural progenitor cells of the dentate gyrus show abnormally high rates of proliferation and genomic instability. Atm(-/-) cells in vivo, and in cell culture, show a blunted response to environmental stimuli that promote neural progenitor cell proliferation, survival, and differentiation along a neuronal lineage. This study defines a role for ATM during the process of neurogenesis, demonstrates that ATM is required for normal cell fate determination and neuronal survival both in vitro and in vivo, and points to a mechanism for neuronal cell loss in progressive neurodegenerative diseases.