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PMID: 17476307 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

BRCA2 is required for neurogenesis and suppression of medulloblastoma.

The EMBO journal ·Vol. 26 ·No. 11 ·2007-06-06 ·Pages 2732-42

Frappart PO, Lee Y, Lamont J, McKinnon PJ

Abstract

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.

MeSH Terms
Animals Apoptosis/genetics,physiology Ataxia Telangiectasia Mutated Proteins BRCA2 Protein/genetics,metabolism Cell Cycle Proteins Cerebellum/cytology,embryology,metabolism DNA Repair/genetics DNA-Binding Proteins/deficiency Gene Silencing Histones/metabolism Immunohistochemistry Karyotyping Medulloblastoma/genetics Mice Phenotype Protein Serine-Threonine Kinases/deficiency Tumor Suppressor Protein p53/deficiency Tumor Suppressor Proteins/deficiency
Chemicals
BRCA2 Protein BRCA2 protein, mouse Cell Cycle Proteins DNA-Binding Proteins Histones Tumor Suppressor Protein p53 Tumor Suppressor Proteins gamma-H2AX protein, mouse Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Frappart Pierre-Olivier
Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lee Youngsoo
Lamont Jayne
McKinnon Peter J
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601703
Published
2007-06-06
Epub
2007-00-03
Pages
2732-42
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1888666
Subset
IM
Grants
NINDS NIH HHS · R56 NS037956 · United States
NINDS NIH HHS · R01 NS037956 · United States
NCI NIH HHS · CA21765 · United States
NINDS NIH HHS · NS37956 · United States
NCI NIH HHS · P30 CA21765 · United States
NCI NIH HHS · P30 CA021765 · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7601703 PMC Full Text View journal details
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