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Contributed by Inder M. Verma, January 29, 2014 (sent for review October 31, 2013; reviewed by David M. Livingston and Thomas M. Jessell)
Significance
The developing brain is highly sensitive to ionizing radiation and DNA damage. Here we report that tumor suppressor breast cancer susceptibility gene 1 (BRCA1) plays a novel role in regulating the embryonic brain development and postnatal brain size. We found that loss of BRCA1 induces p53-dependent proapoptotic pathways in the CNS. BRCA1 possibly functions as a centrosomal factor in establishing the cellular polarity of the neural progenitors through the DNA damage sensor kinase ATM. Our data provide new insight in understanding the control of DNA damage sensitivity and brain size during development and evolution.
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.
Footnotes
↵1G.M.P., Q.Z., and C.G.P.-G. contributed equally to the work.
↵2Present address: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
↵3Present address: Stem Cells and Regenerative Medicine, Lerner Research Institute/Cleveland Clinic, Cleveland, OH 44195.
- ↵4To whom correspondence should be addressed. E-mail: verma{at}salk.edu.
Author contributions: G.M.P., Q.Z., C.G.P.-G., F.H.G., D.D.M.O., and I.M.V. designed research; G.M.P., Q.Z., C.G.P.-G., S.-J.C., and H.S. performed research; G.M.P., Q.Z., C.G.P.-G., H.S., F.H.G., D.D.M.O., and I.M.V. analyzed data; and G.M.P., Q.Z., C.G.P.-G., and I.M.V. wrote the paper.
The authors declare no conflict of interest.
Reviewers: D.M.L., Dana–Farber Cancer Institute; T.M.J., Columbia University.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1400783111/-/DCSupplemental.
Role of BRCA1 in brain development
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