The Interleukin 3 Gene (IL3) Contributes to Human Brain Volume Variation by Regulating Proliferation and Survival of Neural Progenitors

Xiong-Jian Luo,Mark Rijpkema,Min Deng,Venkata S Mattay,Kun Xiang,Guillén Fernández,Ming Li,Li Shen,Andrew J Saykin,Qiang Chen,Liang Huang,Kwangsik Nho,Daniel R Weinberger,Barbara Franke,Bing Su,Xiao Xiao,Lin Gan,Jingchun Chen ,Yang Li ,Jinkai Wang ,Alejandro Arias Vásquez ,Xiangyu Cao ,Xuebin Qi ,Xiaodong Shi ,Xiangning Chen ,Yingmei Peng

doi:10.1371/journal.pone.0050375

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.

Highlights

The greatly expanded brain size and highly developed cognitive abilities are the most significant features that set humans apart from other species
For the initial analyses in Chinese population, we performed a genetic screening to detect the association of cranial volume with sequence variations located in the 5q23.2–33.1 region
To test whether schizophrenia susceptibility variants in 5q23.2–33.1 are associated with brain volume, we initially genotyped 8 tagging single nucleotide polymorphisms (SNPs) covering the four genes (SPEC2, PDZ-GEF2, LOC728637, and ACSL6)

Summary

Introduction

The greatly expanded brain size and highly developed cognitive abilities are the most significant features that set humans apart from other species. Though the reported microcephalin genes are important in explaining the enlarged human brain during evolution [8], recent studies have indicated that they only account for a small part of brain volume variation in the general population [9,10]. Recent genome wide association studies have identified several promising loci significantly associated with intracranial volume and head circumference [11,12,13]. All of these studies were performed only in populations of European ancestry and some of the variants (e.g., rs7890687 and rs9915547) identified in these GWAS were fixed (monomorphic) in Chinese population, suggesting that additional genes/variants may modulate brain volume variation in Chinese population

Methods

Results

Conclusion