title: Role of BRCA1 in brain development.
abstract: 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.
authors.affiliation: Laboratory of Genetics and Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Pao
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Perez-Garcia
authors.forename: Shen-Ju
authors.initials: SJ
authors.lastname: Chou
authors.forename: Hoonkyo
authors.initials: H
authors.lastname: Suh
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Dennis D M
authors.initials: DD
authors.lastname: O'Leary
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D016764:Cell Polarity; D049109:Cell Proliferation; D002470:Cell Survival; D003071:Cognition / Q000502:physiology; D017353:Gene Deletion; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D064231:Nestin; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse