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Updated: Aug 12, 2026
Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice
Published on: April 3, 2011
Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice
P R Borghesani1, F W Alt, A Bottaro
1Department of Pediatric Oncology and Division of Cellular and Molecular Biology, Dana-Farber Cancer Institute, Boston, MA 00115, USA.
Abstract:
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.
Insights
New Atm mutant mice show cerebellar dysfunction and immune cell development issues, offering insights into hereditary ataxia-telangiectasia (A-T) pathogenesis. These findings advance understanding of A-T disease mechanisms.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Immunology
Background:
- Ataxia-telangiectasia (A-T) is a hereditary disorder characterized by motor incoordination, immune deficiencies, and cancer risk.
- Mutations in the ATM gene are the known cause of A-T.
- Existing Atm mutant mouse models have limitations in fully recapitulating A-T pathology.
Purpose of the Study:
- To generate and characterize a novel line of Atm mutant mice, Atm(y/y), to study ataxia-telangiectasia.
- To investigate the neuropathological and immunological consequences of Atm deficiency in these mice.
- To explore the contribution of Purkinje cell and lymphocyte abnormalities to A-T pathogenesis.
Main Methods:
- Gene targeting was employed to create Atm(y/y) mutant mice.
- Phenotypic analysis included assessment of motor learning, cerebellar structure, and thymocyte development.
- Comparison with existing Atm mutant mouse models was performed.
Main Results:
- Atm(y/y) mice exhibited motor learning deficits, indicating cerebellar dysfunction.
- Ectopic and abnormally differentiated Purkinje cells were observed in the cerebellum of mutant mice.
- A previously unrecognized effect of Atm deficiency on CD4(+)8(+) thymocyte development or maintenance was identified.
- Atm(y/y) mice showed a lower incidence of thymic lymphoma and improved survival compared to other Atm mutant mice.
Conclusions:
- The Atm(y/y) mouse model displays key neuropathological abnormalities relevant to human ataxia-telangiectasia.
- Atm deficiency impacts both cerebellar development (Purkinje cells) and immune cell populations (thymocytes).
- Abnormal development of Purkinje cells and lymphocytes is likely a significant contributor to A-T pathogenesis.
