title: The interleukin 3 gene (IL3) contributes to human brain volume variation by regulating proliferation and survival of neural progenitors.
abstract: 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.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Xiong-jian
authors.initials: XJ
authors.lastname: Luo
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vasquez
authors.forename: Mark
authors.initials: M
authors.lastname: Rijpkema
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Guillén
authors.initials: G
authors.lastname: Fernández
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Jing-chun
authors.initials: JC
authors.lastname: Chen
authors.forename: Xiang-ning
authors.initials: XN
authors.lastname: Chen
authors.forename: Jin-Kai
authors.initials: JK
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Xue-bin
authors.initials: XB
authors.lastname: Qi
authors.forename: Kun
authors.initials: K
authors.lastname: Xiang
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Peng
authors.forename: Xiang-yu
authors.initials: XY
authors.lastname: Cao
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Shi
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology* / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics* / Q000378:metabolism; D053650:Interleukin-3 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009929:Organ Size; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: C508596:IL3 protein, human; C115022:IL3RA protein, human; D007377:Interleukin-3; D053650:Interleukin-3 Receptor alpha Subunit; D011960:Receptors, Estrogen