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Atm-null mice exhibit enhanced radiation-induced birth defects and a hybrid form of embryonic programmed cell death

Rebecca R Laposa1, Jeffrey T Henderson, Elaine Xu

  • 1Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 23, 2004
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) acts as a teratologic suppressor gene. Atm-null embryos are highly susceptible to radiation, leading to birth defects and lethality, highlighting ATM's role in preventing DNA damage-induced teratogenesis.

Area of Science:

  • Genetics
  • Developmental Biology
  • Radiation Biology

Background:

  • The ataxia-telangiectasia mutated (ATM) protein is a key transducer of genotoxic stress.
  • ATM plays a critical role in DNA damage response pathways.

Purpose of the Study:

  • To investigate the role of ATM in embryonic development and its susceptibility to radiation-induced teratogenesis.
  • To determine if ATM deficiency leads to birth defects and embryonic lethality.

Main Methods:

  • Utilized Atm-null mouse embryos to assess radiosensitivity and teratogenic outcomes.
  • Exposed wild-type and Atm-null embryos to varying doses of ionizing radiation (0.5 Gy and 2 Gy).
  • Analyzed p53 protein levels and apoptosis in the central nervous system (CNS) post-irradiation.

Main Results:

  • Atm-null embryos exhibited severe runting, tail anomalies, and lethality after exposure to low-dose (0.5 Gy) radiation.
  • Radiation treatment induced p53 protein elevation and CNS apoptosis in wild-type mice, but not in Atm-null mutants, at 6 hours postirradiation.
  • A reversal of this pattern was observed at 48 hours, with Atm-null mice showing increased programmed cell death in the CNS.
  • Heterozygous Atm-deficient embryos also demonstrated radiosensitivity at a higher dose (2 Gy).

Conclusions:

  • ATM functions as a novel teratologic suppressor gene, protecting embryos from pathological cell death and birth defects.
  • Embryonic susceptibility to DNA damage-induced teratogenesis is significantly influenced by ATM status.
  • ATM deficiency compromises embryonic development, particularly in response to genotoxic stress.

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