Ataxia telangiectasia mutated is essential during adult neurogenesis

被引:135
作者
Allen, DR
van Praag, H
Ray, J
Weaver, Z
Winrow, CJ
Carter, TA
Braquet, R
Harrington, E
Ried, T
Brown, KD
Gage, FH
Barlow, C
机构
[1] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA
[2] NCI, Dept Genet, Div Clin Sci, NIH, Bethesda, MD 20892 USA
[3] Louisiana State Univ, Med Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA
[4] Louisiana State Univ, Med Ctr, Stanley S Scott Canc Ctr, New Orleans, LA 70112 USA
[5] Massachusetts Gen Hosp, Mol Oncol Lab, Charlestown, MA 01029 USA
关键词
neural progenitor; DNA repair; neuron; oligodendrocyte; astrocyte; running;
D O I
10.1101/gad.869001
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:554 / 566
页数:13
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