Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice.
Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atm(y/y) mice. In contrast to other Atm mutant mice, Atm(y/y) mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atm(y/y) mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atm(y/y) animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4(+)8(+) thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T.
Borghesani
P R
PR
Department of Pediatric Oncology and Division of Cellular and Molecular Biology, Dana-Farber Cancer Institute, Boston, MA 00115, USA.
Alt
F W
FW
Bottaro
A
A
Davidson
L
L
Aksoy
S
S
Rathbun
G A
GA
Roberts
T M
TM
Swat
W
W
Segal
R A
RA
Gu
Y
Y
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000473:pathology; D004268:DNA-Binding Proteins; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D008017:Life Expectancy; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011597:Psychomotor Performance; D011689:Purkinje Cells / Q000166:cytology*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases