ATR maintains select progenitors during nervous system development

Abstract

The ATR (ATM (ataxia telangiectasia mutated) and rad3-related) checkpoint kinase is considered critical for signalling DNA replication stress and its dysfunction can lead to the neurodevelopmental disorder, ATR-Seckel syndrome. To understand how ATR functions during neurogenesis, we conditionally deleted Atr broadly throughout the murine nervous system, or in a restricted manner in the dorsal telencephalon. Unexpectedly, in both scenarios, Atr loss impacted neurogenesis relatively late during neural development involving only certain progenitor populations. Whereas the Atr-deficient embryonic cerebellar external germinal layer underwent p53-(and p16 Ink4a/Arf )-independent proliferation arrest, other brain regions suffered apoptosis that was partially p53 dependent. In contrast to other organs, in the nervous system, p53 loss did not worsen the outcome of Atr inactivation. Coincident inactivation of Atm also did not affect the phenotype after Atr deletion, supporting non-overlapping physiological roles for these related DNA damage-response kinases in the brain. Rather than an essential general role in preventing replication stress, our data indicate that ATR functions to monitor genomic integrity in a selective spatiotemporal manner during neurogenesis.

The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors

“…9). These results are in agreement with the reported requirements for p53 in the apoptotic death of neural progenitors with abnormal cell cycle progression induced by p57 Kip2 or Atr inactivation 42,43 . In fact, p53 loss has been shown to exacerbate the effects of DNA replication defects in several models [44][45][46] , further supporting the idea that the primary defect in Cdh1-deficient cells is related to abnormal DNA replication.…”

DNA strand break repair and neurodegeneration

“…In this model, the severe loss of neurons throughout the cerebellum, hippocampus and cortex correlates with areas of neurogenesis in the developing brain, with cell death arising from replication stress in the absence of ATR activity [56]. Similarly, a brain-specific ATR knockout suggested that ATR signalling in the brain is critical during rapid waves of neuroprogenitor cell division in the GE and cerebellum at late stages of development [57]. Other mutant proteins, such as pericentrin and MCPH1 have been implicated in the cause of microcephaly through coupling ATR signalling to the G2/M checkpoint via the centrosome [58,59].…”

Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth

“…CGNPs are highly sensitive to apoptosis in response to genotoxic stress (Chong et al, 2000;Lee et al, 2012). The mitotic abnormalities in Aspm-deficient CGNPs, and prior studies demonstrating a role for Aspm in mitotic spindle dynamics (Zhong et al, 2005;Fish et al, 2006;Higgins et al, 2010) and DNA repair (Kato et al, 2011) suggest that increased CGNP apoptosis in Aspm mutants might be caused by increased DNA damage.…”