Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system.

Ataxia telangiectasia (AT) is characterized by progressive neurodegeneration that results from mutation of the ATM gene. However, neither the normal function of ATM in the nervous system nor the biological basis of the degeneration in AT is known. Resistance to apoptosis in the developing central nervous system (CNS) of Atm-/- mice was observed after ionizing radiation. This lack of death occurred in diverse regions of the CNS, including the cerebellum, which is markedly affected in AT. In wild-type, but not Atm-/- mice, up-regulation of p53 coincided with cell death, suggesting that Atm-dependent apoptosis in the CNS is mediated by p53. Further, p53 null mice showed a similar lack of radiation-induced cell death in the developing nervous system. Atm may function at a developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage.

[1]  Y. Shiloh,et al.  Ataxia-telangiectasia: is ATM a sensor of oxidative damage and stress? , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[2]  D. Baltimore,et al.  Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation , 1997, Nature.

[3]  O. Steward,et al.  Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  R. Weichselbaum,et al.  Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Y. Shiloh,et al.  The genetic defect in ataxia-telangiectasia. , 1997, Annual review of immunology.

[6]  D. Baltimore,et al.  Dual roles of ATM in the cellular response to radiation and in cell growth control. , 1996, Genes & development.

[7]  S. Aizawa,et al.  Involvement of p53 in DNA Strand Break‐induced Apoptosis in Postmitotic CNS Neurons , 1996 .

[8]  N. Heintz.  Ataxia telangiectasia: cell signaling, cell death and the cell cycle , 1996, Current opinion in neurology.

[9]  M. Lovett,et al.  A single ataxia telangiectasia gene with a product similar to PI-3 kinase. , 1995, Science.

[10]  T. Jacks,et al.  A subset of p53-deficient embryos exhibit exencephaly , 1995, Nature Genetics.

[11]  Scott W. Lowe,et al.  p53 is required for radiation-induced apoptosis in mouse thymocytes , 1993, Nature.

[12]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[13]  J. Bartek,et al.  Analysis of p53 expression in human tumours: an antibody raised against human p53 expressed in Escherichia coli. , 1992, Journal of cell science.

[14]  R. Bronson,et al.  Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene , 1991, Cell.

[15]  R. Oppenheim.  Cell death during development of the nervous system. , 1991, Annual review of neuroscience.

[16]  Constance L. Cepko,et al.  A common progenitor for neurons and glia persists in rat retina late in development , 1987, Nature.

[17]  W. Cowan,et al.  Chapter 5 The Development of The Dentate Gyrup , 1980 .