From the Cover: Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice

Abstract

The autosomal recessive disease ataxia–telangiectasia (A-T) is characterized by the early onset of progressive ataxia, ocular telangiectasias, and susceptibility to infections and tumors (1, 2). A-T is caused by mutations in the ATM gene (3). The ATM protein encodes a serine/threonine kinase and induces p53, c-Abl, and Brca1 activation after DNA damage (4–8). ATM-deficient cells exhibit cell-cycle checkpoint defects, resulting in hypersensitivity to genotoxic stress (9). However, it is less clear whether the abnormal cellular physiology of various ATM-deficient cell types also results from defective DNA repair. For example, potassium-mediated depolarization is attenuated in A-T fibroblasts (10), and calcium mobilization and phospholipase-Cγ activation are reduced in A-T B cells after antigen receptor stimulation (11). Altered cellular physiology may independently contribute to the clinical manifestations of A-T. Several lines of Atm mutant mice recapitulate numerous aspects of A-T (12–15). These Atm mutant mice exhibit growth retardation, immune system defects including defects in T cell maturation, germ cell dysfunction, and increased sensitivity to ionizing radiation (IR). Although behavioral abnormalities were observed (14), altered cerebellar histology or degeneration was not reported (12–15). The diversity of ATM mutations and the variability in the clinical progression of A-T raises questions concerning how individual ATM mutations and genetic factors contribute to the clinical severity of A-T. Likewise, independently generated Atm-deficient mice may also vary in their phenotypic manifestations, reflecting mutagenesis strategies and/or genetic backgrounds. Murine Atm is expressed in both embryonic and adult tissues and likely functions at multiple developmental stages (16). It remains unclear whether Atm deficiency alters developmental processes and how this may contribute to neurodegeneration and immunodeficiency in A-T patients. Clinical studies documenting the early onset of ataxia (17–19) and early abnormalities in Purkinje cell morphology and localization (20, 21) support the hypothesis that ATM function is essential for normal cerebellar development. To further evaluate the potential Atm functions, we have generated and characterized a line of Atm mutant mice.