BRCA2 is required for neurogenesis and suppression of medulloblastoma.
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, Brca2(LoxP/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 Brca2(LoxP/LoxP);Nestin-cre mice showed extensive gammaH2AX 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.
Frappart
Pierre-Olivier
PO
Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lee
Youngsoo
Y
Lamont
Jayne
J
McKinnon
Peter J
PJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D007621:Karyotyping; D008527:Medulloblastoma / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D025521:Tumor Suppressor Proteins / Q000172:deficiency
D024682:BRCA2 Protein; C106711:BRCA2 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases