神經(jīng)系統(tǒng)是人類區(qū)別于其他物種最顯著的特征之一,。相對于其他物種，人類的大腦高度發(fā)達(dá)，主要體現(xiàn)在全腦容量的變化,。如人類的大腦容量是舊大陸猴-如獼猴腦容量的20.6倍,，長臂猿的14.4倍，與人類親緣關(guān)系最近的靈長類-黑猩猩的4.3倍,。近年來，基于核磁共振（MRI）腦影像學(xué)研究表明腦容量具有很高的遺傳力,，并且與智商和記憶等認(rèn)知能力高度相關(guān),；除此之外，腦容量在多種精神疾?。ㄈ缇穹至寻Y）患者中均發(fā)生了明顯病變,，因此了解腦容量的遺傳基礎(chǔ)對于我們理解精神疾病的發(fā)病機(jī)制以及神經(jīng)發(fā)生的分子機(jī)制都具有重要的意義。然而,，即便有如此高的遺傳力,，截止到目前為止，僅僅只有少數(shù)幾個基因被發(fā)現(xiàn)與腦容量相關(guān),。
為了尋找可能影響腦容量變化的基因,，昆明動物研究所宿兵研究員的實(shí)驗(yàn)室（羅雄劍和李明）選取了50個精神分裂癥易感基因，并在中國漢族人群中分析了它們與腦容量的關(guān)系,，最終發(fā)現(xiàn)位于染色體5q23.2-33.1區(qū)域的SNP位點(diǎn)（rs31480等）與腦容量強(qiáng)烈相關(guān),。隨后，通過國際合作,，他們在歐洲人群中也重復(fù)了這一結(jié)果,。進(jìn)一步的體外功能實(shí)驗(yàn)證明，rs31480位于白介素-3（IL3）基因啟動子區(qū)并影響轉(zhuǎn)錄因子Sp1的結(jié)合能力,，從而上調(diào)白介素3基因的轉(zhuǎn)錄,。對小鼠的分析發(fā)現(xiàn)，白介素-3及其受體在發(fā)育中的小鼠大腦中持續(xù)表達(dá),，并在出生后1-4天達(dá)到峰值,，這一時期也是神經(jīng)發(fā)生和增殖的重要時期。他們進(jìn)一步發(fā)現(xiàn)白介素3受體主要在小鼠的神經(jīng)前體細(xì)胞中表達(dá),，并且白介素-3能夠促進(jìn)神經(jīng)前體細(xì)胞的增殖和存活能力,。這些結(jié)果揭示了白介素3除了在免疫系統(tǒng)中的已知功能之外，還參與中樞神經(jīng)系統(tǒng)的發(fā)育從而影響腦容量,。除此之外,，通過體外實(shí)驗(yàn)，他們還發(fā)現(xiàn)了白介素-3基因性別特異性相關(guān)的可能機(jī)制,，即它可以活化雌激素受體,，并誘導(dǎo)下游的信號通路。相關(guān)工作于11月30日發(fā)表在PLoS One雜志上（生物谷Bioon.com）
doi:10.1371/journal.pone.0050375
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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.
