神经系统是人类区别于其他物种最显著的特征之一。相对于非人灵长类物种，人类的大脑高度发达，主要体现在脑容量的变化。如人类的大脑容量是猕猴脑容量的20.6倍，长臂猿的14.4倍，黑猩猩的4.3倍。最近，中科院昆明动物所的科技人员发现了影响人类大脑容量的新基因。
近年来，核磁共振（MRI）脑影像学研究表明，脑容量具有很高的遗传力，并且与智商和记忆等认知能力高度相关。另外，脑容量在多种精神疾病（如精神分裂症）患者中均发生了明显病变，因此了解脑容量的遗传基础对于人类研究精神疾病的发病机制以及神经发生的分子机制都具有重要的意义。然而，即便有如此高的遗传力，截止到目前为止，仅仅只有少数几个基因被发现与脑容量相关。
为了寻找可能影响脑容量变化的基因，中科院昆明动物研究所宿兵研究员的实验室的科研人员选取了50个精神分裂症易感基因，并在中国汉族人群中分析了它们与脑容量变异的关系，最终发现位于5号染色体长臂23.2-33.1区域的序列变异位点（rs31480等）与脑容量强烈相关。随后，通过国际合作，他们在欧洲人群中也重复了这一结果。
进一步的体外功能实验证明，序列变异位点rs31480位于白介素-3（IL3）基因启动子区，并能够影响转录因子Sp1的结合能力，从而上调白介素-3基因的表达。对小鼠体内的分析发现，白介素-3及其受体主要在发育中的小鼠的神经前体细胞中表达，并且白介素-3能够促进神经前体细胞的增殖和存活能力。这些结果揭示了白介素3除了在免疫系统中的已知功能之外，还参与中枢神经系统的发育从而影响脑容量。
该研究成果近日发表在PLoS One（美国公共图书馆杂志综合）杂志上。
The Interleukin 3 Gene (IL3) Contributes to Human Brain Volume Variation by Regulating Proliferation and Survival of Neural Progenitors
Xiong-jian Luo, Ming Li, Liang Huang, Kwangsik Nho,, Min Deng, Qiang Chen, Daniel R. Weinberger, Alejandro Arias Vasquez, Mark Rijpkema, Venkata S. Mattay, Andrew J. Saykin,, Li Shen,, Guillén Fernández, Barbara Franke, Jing-chun Chen, Xiang-ning Chen, Jin-kai Wang, Xiao Xiao, Xue-bin Qi, Kun Xiang, Ying-Mei Peng, Xiang-yu Cao, Yi Li, Xiao-dong Shi, for the Alzheimer’s Disease Neuroimaging Initiative , Lin Gan, Bing Su
One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1–4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn’t directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development.
