Pulvers Jeremy N, Huttner Wieland B
Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Development. 2009 Jun;136(11):1859-68. doi: 10.1242/dev.033498. Epub 2009 Apr 29.
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.
已知神经祖细胞的凋亡程度会影响大脑皮层的大小。缺乏人类乳腺癌易感基因BRCA1的直系同源基因Brca1的小鼠胚胎，在神经管中会出现凋亡现象，但这对大脑发育的影响尚未得到研究。在这里，我们通过使用Emx1-Cre删除floxed Brca1，研究了Brca1在小鼠胚胎皮质发育过程中的作用，这会导致在胚胎第9.5天（E）后，背侧端脑特异性地进行条件性基因敲除。出生后Brca1敲除的大脑皮层在皮质厚度和表面积方面均显著减小。值得注意的是，尽管皮质层（最上层除外）的厚度有所减小，但皮质分层本身基本未受干扰。在E11.5和E13.5时发现高水平的凋亡，但到E16.5时降至接近对照水平。神经发生早期的凋亡发生在BrdU脉冲标记的神经祖细胞及其衍生的神经元中。在顶端（神经上皮、放射状胶质）祖细胞和基底（中间）祖细胞的有丝分裂指数上未观察到变化，这表明Brca1敲除不影响细胞周期进程。然而，Brca1敲除确实导致神经祖细胞中p53的核转位，这表明它们的凋亡涉及p53途径激活。我们的结果表明，Brca1通过防止早期皮质祖细胞及其直接后代的凋亡，是大脑皮层发育到正常大小所必需的。
