Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status

J Neurosci. 2001 Sep 1;21(17):6687-93. doi: 10.1523/JNEUROSCI.21-17-06687.2001.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Apoptosis / radiation effects*
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia Mutated Proteins
  • Caspase 3
  • Caspases / metabolism
  • Cell Cycle Proteins
  • Cell Differentiation / physiology
  • Cell Differentiation / radiation effects
  • Cell Division / genetics
  • Cell Division / radiation effects
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / radiation effects
  • Female
  • Gamma Rays*
  • Mice
  • Mice, Knockout
  • Mitosis / radiation effects
  • Nervous System / cytology*
  • Nervous System / embryology
  • Nervous System / metabolism
  • Nervous System / radiation effects*
  • Neurons / cytology
  • Neurons / radiation effects
  • Phosphorylation / radiation effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Retina / cytology
  • Retina / growth & development
  • Retina / radiation effects
  • Stem Cells / cytology
  • Stem Cells / radiation effects
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases