Ataxia telangiectasia mutated is essential during adult neurogenesis

  1. Duane M. Allen1,6,
  2. Henriette van Praag1,6,
  3. Jasodhara Ray1,
  4. Zoë Weaver2,
  5. Christopher J. Winrow1,
  6. Todd A. Carter1,
  7. Ray Braquet3,
  8. Elizabeth Harrington4,
  9. Thomas Ried2,
  10. Kevin D. Brown3,
  11. Fred H. Gage1, and
  12. Carrolee Barlow1,5
  1. 1The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA; 2Genetics Department, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; 3Department of Biochemistry and Molecular Biology and The Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, Louisiana 70112, USA; 4Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 01029, USA

Abstract

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.

Keywords

Footnotes

  • 5 Corresponding author.

  • 6 These authors contributed equally to this work.

  • E-MAIL barlow{at}salk.edu; FAX (858) 558-7454.

  • Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.869001.

    • Received November 22, 2000.
    • Accepted January 8, 2001.
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