Ataxia Telangiectasia Mutated-Dependent Apoptosis after Genotoxic Stress in the Developing Nervous System Is Determined by Cellular Differentiation Status

Abstract

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.

Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice

“…To further confirm that Trp53 515C/515C mutants were unable to induce apoptosis in vivo, we irradiated 13.5-day-old embryos and analyzed p53-dependent apoptosis in the central nervous system. As expected, apoptosis was widespread in wild-type embryos but was not detected in the Trp53-null embryos 12 or in Trp53 515C/515C mutants (Fig. 3f).…”

DNA double-strand break repair and development

“…Post-mitotic neurons of the developing CNS and the dorsal root ganglia of postnatal Atm À/À mice were resistant to irradiation-induced apoptosis in comparison to wild-type animals. Consistent with the lack of apoptosis, p53 stabilization was drastically attenuated in the radioresistant Atm À/À tissues and there was a similar lack of apoptosis post-irradiation in p53-null animals (Herzog et al, 1998; Chong et al, 2000; Lee et al, 2001). Chk2, Puma and Bax deficiencies have also been shown to abrogate DNA DSB-induced apoptosis in the developing nervous system (Chong et al, 2000;Takai et al, 2002;Jeffers et al, 2003).…”

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

“…McKinnon and colleagues [26] have shown that in mice, the ATM protein is required for triggering apoptosis in response to neuronal DNA damage during the period shortly after the stage of terminal differentiation. Importantly, however, this observation does not exclude an ongoing role of the ATM protein in Purkinje neurons at later stages (see [27]).…”