神经系统是人类区别于其他物种最显著的特征之一。相对于其他物种，人类的大脑高度发达，主要体现在全脑容量的变化。如人类的大脑容量是旧大陆猴-如猕猴脑容量的20.6倍，长臂猿的14.4倍，与人类亲缘关系最近的灵长类-黑猩猩的4.3倍。近年来，基于核磁共振（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；除此之外，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我们理解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，昆明动物研究所宿兵研究员的实验室（罗雄剑和李明）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的关系，最终发现位于染色体5q23.2-33.1区域的SNP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，rs31480位于白介素-3（IL3）基因启动子区并影响转录因子Sp1的结合能力，从而上调白介素3基因的转录。对小鼠的分析发现，白介素-3及其受体在发育中的小鼠大脑中持续表达，并在出生后1-4天达到峰值，这一时期也是神经发生和增殖的重要时期。他们进一步发现白介素3受体主要在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。除此之外，通过体外实验，他们还发现了白介素-3基因性别特异性相关的可能机制，即它可以活化雌激素受体，并诱导下游的信号通路。相关工作于11月30日发表在PLoS One杂志上（生物谷Bioon.com）
doi:10.1371/journal.pone.0050375
PMC:
PMID:
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.
