Ataxia telangiectasia mutated is essential during adult neurogenesis.
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.
The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
D M
DM
Allen
H
H
van Praag
J
J
Ray
Z
Z
Weaver
C J
CJ
Winrow
T A
TA
Carter
R
R
Braquet
E
E
Harrington
T
T
Ried
K D
KD
Brown
F H
FH
Gage
C
C
Barlow
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development; D015536:Down-Regulation; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000166:cytology*; D010641:Phenotype; D010805:Physical Conditioning, Animal; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases