关键词： 乳腺癌 基因 大脑尺寸 控制
一项研究提出，一个涉及乳腺和卵巢癌风险的基因BRCA1可能在控制哺乳动物的大脑尺寸方面起到了作用。
乳腺癌易感基因1（BRCA1）是一个肿瘤抑制基因，已知它能够影响乳腺和卵巢癌风险，但是能帮助修复DNA损伤的BRCA1蛋白质在胚胎的频繁分裂的神经上皮细胞和干细胞中高度表达。
为了确定BRCA1在胚胎神经前体中的功能重要性，InderVerma及其同事培育出了胚胎大脑缺乏BRCA1的转基因小鼠，结果发现这种突变小鼠的大脑的涉及认知、记忆、运动控制和感觉的几个片层结构——也就是新皮层、小脑、海马区以及嗅球——表现出了几种缺陷，包括细胞死亡和组织体积流失。
这组作者发现实验删除肿瘤抑制基因p53能部分恢复缺乏BRCA1的小鼠受影响的大脑结构的正常片层化，这很可能是由于BRCA1的消失导致了p53调控的神经元前体细胞死亡。然而，只有在称为ATM的另一种信号传导蛋白被删除之后，BRCA1突变型小鼠的特定的神经元类型的细胞极性和中心体——参与细胞分裂的细胞器——的缺陷才被修正。这些发现提示了一个模型，在这个模型中，BRCA1位于DNA修复和中心体功能的交汇处，这些功能是由p53和ATM参与的一个信号传导级联调控的，它很可能控制着大脑体积。
这组作者说，BRCA1基因可能进化成了控制灵长类动物的大脑尺寸和结构。
Proceedings of the National Academy of the Sciences of the United States of America doi: 10.1073/pnas.1400783111
Role of BRCA1 in brain development
Gerald M. Paoa，1，QuanZhua，1， Carlos G. Perez-Garciab，1， Shen-JuChoub，2，HoonkyoSuha，3， Fred H. Gagea， Dennis D. M. O’Learyb， and Inder M. Vermaa，4
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.
（由徐沁整理）