Brca1 is required for embryonic development of the mouse cerebral cortex to normal size by preventing apoptosis of early neural progenitors

Abstract

The extent of apoptosis of neural progenitors is known to influence the size of the cerebral cortex. Mouse embryos lacking Brca1, the ortholog of the human breast cancer susceptibility gene BRCA1, show apoptosis in the neural tube, but the consequences of this for brain development have not been studied. Here we investigated the role of Brca1 during mouse embryonic cortical development by deleting floxed Brca1 using Emx1-Cre, which leads to conditional gene ablation specifically in the dorsal telencephalon after embryonic day (E) 9.5. The postnatal Brca1-ablated cerebral cortex was substantially reduced in size with regard to both cortical thickness and surface area. Remarkably, although the thickness of the cortical layers (except for the upper-most layer) was decreased, cortical layering as such was essentially unperturbed. High levels of apoptosis were found at E11.5 and E13.5, but dropped to near-control levels by E16.5. The apoptosis at the early stage of neurogenesis occurred in both BrdU pulse-labeled neural progenitors and the neurons derived therefrom. No changes were observed in the mitotic index of apical (neuroepithelial, radial glial) progenitors and basal (intermediate) progenitors, indicating that Brca1 ablation did not affect cell cycle progression. Brca1 ablation did, however, result in the nuclear translocation of p53 in neural progenitors, suggesting that their apoptosis involved activation of the p53 pathway. Our results show that Brca1 is required for the cerebral cortex to develop to normal size by preventing the apoptosis of early cortical progenitors and their immediate progeny. Development 136, 1859Development 136, -1868Development 136, (2009Development 136, ) doi:10.1242 Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. . Brca1 is widely expressed in proliferating tissues and is also expressed in the ventricular neuroepithelium of the neural tube (Korhonen et al., 2003). KEY WORDS: Brca1, Apoptosis, Cerebral cortexThe relevance of apoptosis in cortical development (Haydar et al., 1999), the increased apoptosis of neuroepithelial cells observed in systemic Brca1 knockouts (Gowen et al., 1996;Xu et al., 2001), and the expression pattern of Brca1 in neural progenitors, when considered together, raise the intriguing possibility that Brca1 might have a role in the development of the cerebral cortex. Moreover, the apparent link between BRCA1 and the primary microcephaly genes ASPM (Bond et al., 2002;Zhong et al., 2005) and MCPH1 (Xu et al., 2004;Lin et al., 2005), whereby knockdown of either microcephaly gene leads to a decrease in BRCA1 levels, also leads to the question of whether BRCA1 has a role in brain size regulation. In this context, it is interesting to note that BRCA1 has undergone positive selection in the primate lineage (Huttley et al., 2000), raising the possibility that it might have been selected owing to a function in brain development. Here, we have investigated this issue by conditional ablation of Brca1 in cor...

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