Ataxia telangiectasia (AT) is characterized by progressive neurodegeneration that results from mutation of the ATM gene. However, neither the normal function of ATM in the nervous system nor the biological basis of the degeneration in AT is known. Resistance to apoptosis in the developing central nervous system (CNS) of Atm-/- mice was observed after ionizing radiation. This lack of death occurred in diverse regions of the CNS, including the cerebellum, which is markedly affected in AT. In wild-type, but not Atm-/- mice, up-regulation of p53 coincided with cell death, suggesting that Atm-dependent apoptosis in the CNS is mediated by p53. Further, p53 null mice showed a similar lack of radiation-induced cell death in the developing nervous system. Atm may function at a developmental survival checkpoint that serves to eliminate neurons with excessive DNA damage.

We show here that a zinc finger transcriptional repressor, Slug, which is aberrantly upregulated by the E2A-HLF oncoprotein in pro-B cell acute leukemia, functions as an antiapoptotic factor in normal hematopoietic progenitor cells. Slug(-/-) mice were much more radiosensitive than wild-type mice, dying earlier and showing accentuated decreases in peripheral blood cell counts, as well as abundant microhemorrhages and widely disseminated bacterial microabscesses throughout the body. Slug expression was detected in diverse subsets of hematopoietic progenitors, but not in more differentiated B and T lymphoid cells, and there was a significant increase in apoptotic (TUNEL-positive) bone marrow progenitor cells in irradiated Slug(-/-) mice compared to wild-type controls. These results implicate Slug in a novel survival pathway that protects hematopoietic progenitors from apoptosis after DNA damage.

Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR). Although many of the same regions of the CNS in both Bax؊͞؊ and Atm؊͞؊ mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IRinduced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm-and Bax-independent branches. Further, Atm-and Bax-dependent apoptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways.T he human syndrome ataxia telangiectasia (A-T) results from mutations of the ATM gene and is characterized by progressive neurodegeneration that leads to severe ataxia (1). A-T is also typified by many other defects including immune deficiencies, cancer proneness, chromosomal instability, and ionizing radiation sensitivity (2). ATM is a large 370-kDa protein that contains a COOH-terminal domain similar to phosphatidylinositol 3-kinase and encodes a protein kinase activity specific for serine and threonine residues (2). This COOH region is conserved throughout a family of proteins that are involved in cellular responses to DNA damage and maintenance of genomic stability. Because a nervous system lesion is the most prevalent feature of A-T, ATM signaling in this tissue is particularly relevant for understanding ATM function in a biological context. The neurological defect(s) in A-T becomes apparent early in life, suggesting that it originates during development. Furthermore, Atm is highly expressed in the developing nervous system but only at low levels in the adult CNS (3). However, the mechanism of neuronal cell loss in A-T is unknown. To this end, we have investigated Atm signaling in the developing CNS of Atm-null mice. Apoptosis resulting from genotoxic damage of the nervous system requires Atm (4), suggesting Atm-dependent apoptosis may be important for the development and maintenance of the nervous system. However, there is a paucity of data concerning other death effectors in this signaling pathway. Therefore, we examined the death effector Bax and the caspases for their role in Atm-dependent apoptosis in the nervous system. Bax is a member of the Bcl-2 family of proteins and functions a...

Ataxia-telangiectasia (A-T) is a neurodegenerative syndrome resulting from dysfunction of ATM (ataxia telangiectasia mutated). The molecular details of ATM function in the nervous system are unclear, although the neurological lesions in A-T are probably developmental because they appear during childhood. The nervous systems of Atm-null mice show a pronounced defect in apoptosis that is induced by DNA damage, suggesting that ATM may function to eliminate DNA-damaged neurons. Here we show that Atm-dependent apoptosis occurs at discrete stages of neurogenesis. Analysis of gamma-irradiated mouse embryos showed that Atm-dependent apoptosis occurred only in the postmitotic populations that were present in the neuroepithelial subventricular zone of the developing nervous system. Notably, Atm deficiency did not prevent radiation-induced apoptosis in multipotent precursor cells residing in the proliferating ventricular zone. Atm-dependent apoptosis required p53 and coincided with the specific phosphorylation of p53 and caspase-3 activation. Thus, these data show that Atm functions early in neurogenesis and underscore the selective requirement for Atm in eliminating damaged postmitotic neural cells. Furthermore, these data demonstrate that the differentiation status of neural cells is a critical determinant in the activation of certain apoptotic pathways.

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