Atm-null mice exhibit enhanced radiation-induced birth defects and a hybrid form of embryonic programmed cell death indicating a teratological suppressor function for ATM.
ATM (ataxia-telangiectasia mutated) is a genotoxic stress transducer. In this first report of Atm-dependent birth defects, Atm-null embryos were uniquely susceptible to low-dose (0.5 Gy) radiation, exhibiting severe runting, tail anomalies, and lethality, independent of cell cycle arrest or insulin-like growth factor 1. This treatment enhanced levels of p53 protein and central nervous system (CNS) apoptosis in wild-type mice, but not Atm-null mutants, at 6 h postirradiation. At 48 h, however, this pattern was reversed, with Atm-null mice exhibiting high levels of a hybrid form of programmed cell death within the CNS. Even heterozygous Atm-deficient embryos were radiosensitive to a higher radiation dose of 2 Gy. These results show that Atm is a novel teratologic suppressor gene protecting embryos from pathological cell death and teratogenesis initiated by even mild DNA damage.
Laposa
Rebecca R
RR
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Henderson
Jeffrey T
JT
Xu
Elaine
E
Wells
Peter G
PG
D000016:Abnormalities, Radiation-Induced / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D016923:Cell Death; D002455:Cell Division / Q000528:radiation effects; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004622:Embryo, Mammalian / Q000473:pathology / Q000528:radiation effects; D005314:Embryonic and Fetal Development / Q000528:radiation effects*; D004847:Epithelial Cells / Q000528:radiation effects; D005260:Female; D005327:Fetal Resorption / Q000209:etiology; D016158:Genes, p53 / Q000528:radiation effects; D005838:Genotype; D005865:Gestational Age; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D009474:Neurons / Q000528:radiation effects; D011247:Pregnancy; D011836:Radiation Tolerance / Q000235:genetics*; D013623:Tail / Q000002:abnormalities; D013687:Telencephalon / Q000196:embryology / Q000473:pathology / Q000528:radiation effects
D004247:DNA