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| Subject Categories: Differentiation & Death | Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 2732–2742, doi:10.1038/sj.emboj.7601703 Published online 3 May 2007 |
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| BRCA2 is required for neurogenesis and suppression of medulloblastoma |
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| Pierre-Olivier Frappart, Youngsoo Lee, Jayne Lamont and Peter J McKinnon |
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Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA To whom correspondence should be addressed Peter J McKinnon, Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. Tel.: +1 901 495 2700; Fax: +1 901 526 2907; E-mail: peter.mckinnon@stjude.org Received 13 November 2006; Accepted 5 April 2007; Published online 3 May 2007. |
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| Abstract |
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Defective DNA damage responses in the nervous system can result in neurodegeneration or tumorigenesis. Despite the importance of DNA damage signalling, the neural function of many critical DNA repair factors is unclear. BRCA2 is necessary for homologous recombination repair of DNA and the prevention of diseases including Fanconi Anemia and cancer. We determined the role of BRCA2 during brain development by inactivating murine Brca2 throughout neural tissues. In striking contrast to early embryonic lethality after germ-line inactivation, Brca2LoxP/LoxP;Nestin-cre mice were viable. However, Brca2 loss profoundly affected neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arose from DNA damage as Brca2LoxP/LoxP;Nestin-cre mice showed extensive  H2AX in neural tissue and p53 deficiency restored brain histology but lead to rapid formation of medulloblastoma brain tumors. In contrast, loss of the Atm kinase did not markedly attenuate apoptosis after Brca2 loss, but did partially restore cerebellar morphology, supporting a genomic surveillance function for ATM during neurogenesis. These data illustrate the importance of Brca2 during nervous system development and underscore the tissue-specific requirements for DNA repair factors. |
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| Keywords: ATM, BRCA2, homologous recombination, medulloblastoma, neurogenesis |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSDNA instability in the brain: survival of the 'fittest' Nature Medicine News and Views (01 May 2005) RESEARCHBRCA2 is required for neurogenesis and suppression of medulloblastoma The EMBO Journal Article An essential function for NBS1 in the prevention of ataxia and cerebellar defects Nature Medicine Article (01 Jun 2005) Fanconi DNA repair pathway is required for survival and long-term maintenance of neural progenitors The EMBO Journal Article |
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