Pleiotropic defects in ataxia-telangiectasia protein-deficient mice.
We have generated a mouse model for ataxia-telangiectasia by using gene targeting to generate mice that do not express the Atm protein. Atm-deficient mice are retarded in growth, do not produce mature sperm, and exhibit severe defects in T cell maturation while going on to develop thymomas. Atm-deficient fibroblasts grow poorly in culture and display a high level of double-stranded chromosome breaks. Atm-deficient thymocytes undergo spontaneous apoptosis in vitro significantly more than controls. Atm-deficient mice then exhibit many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them. Furthermore, we demonstrate that the Atm protein exists as two discrete molecular species, and that loss of one or of both of these can lead to the development of the disease.
Elson
A
A
Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Wang
Y
Y
Daugherty
C J
CJ
Morton
C C
CC
Zhou
F
F
Campos-Torres
J
J
Leder
P
P
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002678:Chimera; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian; D005091:Exons; D005260:Female; D005347:Fibroblasts; D006580:Genetic Carrier Screening; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007621:Karyotyping; D016350:Leucine Zippers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D012671:Seminiferous Tubules / Q000473:pathology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases