Phenotype Of Atm Knockout Mice

Several different strains of Atm~'~ mice have been generated since the cloning of the ATM gene (96,99,148). The mice all have a similar AT-like phenotypes in that they express neurological abnormalities, immune defects, genetic instability, radiation sensitivity, infertility, and a high incidence of lymphoma. Despite these phenotypic similarities with AT patients, there are differences, including severe growth retardation, universal sterility, and death from lymphoma by age 6 months in Atm~'~ mice (96,99,148). The neurological phenotype of the mice is notable.

Mice Phenotypes

Figure 5 ATM rapidly localizes to DSBs in the nuclei of human fibroblasts. Left panel: DSBs form in the path of a laser microbeam. Right panel: ATM protein localizes to regions of laser-induced DSBs within 15 min following irradiation. [For these images, DSBs were introduced in genomic DNA of human fibroblasts by briefly exposing the cells to Hoechst dye and then irradiating them with a 1 micron diameter beam of 390nm laser light (Ref. 147). DSBs were detected by end labeling with Cy3-tagged dTCP. ATM was identified by immunohistochemical staining using an anti-ATM primary antibody and an FITC-labeled secondary antibody. Both cells were counterstained with DAPI to detect nuclear DNA.] (See color insert.)

Figure 5 ATM rapidly localizes to DSBs in the nuclei of human fibroblasts. Left panel: DSBs form in the path of a laser microbeam. Right panel: ATM protein localizes to regions of laser-induced DSBs within 15 min following irradiation. [For these images, DSBs were introduced in genomic DNA of human fibroblasts by briefly exposing the cells to Hoechst dye and then irradiating them with a 1 micron diameter beam of 390nm laser light (Ref. 147). DSBs were detected by end labeling with Cy3-tagged dTCP. ATM was identified by immunohistochemical staining using an anti-ATM primary antibody and an FITC-labeled secondary antibody. Both cells were counterstained with DAPI to detect nuclear DNA.] (See color insert.)

Like AT patients, Atm~'~ mice have impaired coordination and they share some histopathological abnormalities, including an increased frequency of ectopic Purkinje cells and selective deficiencies of dopaminergic neurons (149,150). However, the cerebellar dysfunction does not appear to be progressive in the Atm~y~ mice (151). Atm~y~ Purkinje cells appear to be normal histologically, and there is not the ongoing, large-scale loss of Purkinje cells from the cerebellum seen in AT patients (152). An electrophysiological study of Atm~'~ mice did find an age-dependent decrease in calcium firing, which was proposed to be an early sign of impending degeneration (152). Nevertheless, the lack of ongoing losses of Purkinje cells and other neurons in the Atm mice has cast a shadow on the suitability of the mice as animal models for the degenerative neurologic disease seen in AT patients.

The essentially universal occurrence of lymphomas in Atm mice in the first 6 months of life appears to be a consequence of aberrant V(D)J recombination, as RAG-1- and RAG-2-deficient mice, which cannot undergo V(DJ) recombination, do not express this early wave of oncogenesis (153,154). However, dysfunctional V(D)J recombination is not the only source of genetic instability leading to lymphomas in ATM-deficient mice, as some Rag2 Atm mice develop lymphomas later in life (154).

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