ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation Journal Article
| Authors: | Lang, P. Y.; Nanjangud, G. J.; Papkov, M. S.; Shaw, C.; Hwang, D.; Parker, J. S.; Kabanov, A. V.; Gershon, T. R. |
| Article Title: | ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation |
| Abstract: | Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastomaprone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest – and, in the absence of p53, non-apoptotic cell death – redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition. © 2016. Published by The Company of Biologists Ltd. |
| Keywords: | mouse; dna damage; medulloblastoma; chromosomal instability; atr; microcephaly; neural progenitor |
| Journal Title: | Development |
| Volume: | 143 |
| Issue: | 21 |
| ISSN: | 0950-1991 |
| Publisher: | Company of Biologists |
| Date Published: | 2016-11-01 |
| Start Page: | 4038 |
| End Page: | 4052 |
| Language: | English |
| DOI: | 10.1242/dev.139022 |
| PROVIDER: | scopus |
| PUBMED: | 27803059 |
| PMCID: | PMC5117143 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 December 2016 -- Source: Scopus |
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