Role of BRCA1 in brain development

Breast cancer susceptibility gene 1 (BRCA1) is a breast and ovarian cancer tumor suppressor whose loss leads to DNA damage and defective centrosome functions. Despite its tumor suppression functions, BRCA1 is most highly expressed in the embryonic neuroepithelium when the neural progenitors are high...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-04, Vol.111 (13), p.E1240-E1248
Main Authors: Pao, Gerald M, Zhu, Quan, Perez-Garcia, Carlos G, Chou, Shen-Ju, Suh, Hoonkyo, Gage, Fred H, O'Leary, Dennis D M, Verma, Inder M
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Ataxia Telangiectasia Mutated Proteins - metabolism
Biological Sciences
Brain - cytology
Brain - embryology
Brain - metabolism
Brain research
BRCA1 Protein - metabolism
Cell Polarity
Cell Proliferation
Cell Survival
Cognition - physiology
Developmental biology
DNA damage
Gene Deletion
Gene expression
Genotype & phenotype
Learning
Mice
Mice, Knockout
Motor Activity - physiology
Nestin - metabolism
Neural Stem Cells - cytology
Neural Stem Cells - metabolism
Phenotype
PNAS Plus
Signal Transduction
Tumor Suppressor Protein p53 - metabolism
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Summary:Breast cancer susceptibility gene 1 (BRCA1) is a breast and ovarian cancer tumor suppressor whose loss leads to DNA damage and defective centrosome functions. Despite its tumor suppression functions, BRCA1 is most highly expressed in the embryonic neuroepithelium when the neural progenitors are highly proliferative. To determine its functional significance, we deleted BRCA1 in the developing brain using a neural progenitor–specific driver. The phenotype is characterized by severe agenesis of multiple laminated cerebral structures affecting most notably the neocortex, hippocampus, cerebellum, and olfactory bulbs. Major phenotypes are caused by excess apoptosis, as these could be significantly suppressed by the concomitant deletion of p53. Certain phenotypes attributable to centrosomal and cell polarity functions could not be rescued by p53 deletion. A double KO with the DNA damage sensor kinase ATM was able to rescue BRCA1 loss to a greater extent than p53. Our results suggest distinct apoptotic and centrosomal functions of BRCA1 in neural progenitors, with important implications to understand the sensitivity of the embryonic brain to DNA damage, as well as the developmental regulation of brain size.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1400783111