title: Estrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates.
abstract: BACKGROUND
  Sexual dimorphism in brain size is common among primates, including humans, apes and some Old World monkeys. In these species, the brain size of males is generally larger than that of females. Curiously, this dimorphism has persisted over the course of primate evolution and human origin, but there is no explanation for the underlying genetic controls that have maintained this disparity in brain size.
  
  
  RESULTS
  In the present study, we tested the effect of the female hormone (estradiol) on seven genes known to be related to brain size in both humans and nonhuman primates, and we identified half estrogen responsive elements (half EREs) in the promoter regions of four genes (MCPH1, ASPM, CDK5RAP2 and WDR62). Likewise, at sequence level, it appears that these half EREs are generally conserved across primates. Later testing via a reporter gene assay and cell-based endogenous expression measurement revealed that estradiol could significantly suppress the expression of the four affected genes involved in brain size. More intriguingly, when the half EREs were deleted from the promoters, the suppression effect disappeared, suggesting that the half EREs mediate the regulation of estradiol on the brain size genes. We next replicated these experiments using promoter sequences from chimpanzees and rhesus macaques, and observed a similar suppressive effect of estradiol on gene expression, suggesting that this mechanism is conserved among primate species that exhibit brain size dimorphism.
  
  
  CONCLUSIONS
  Brain size dimorphism among certain primates, including humans, is likely regulated by estrogen through its sex-dependent suppression of brain size genes during development.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Road, Kunming, 650223, Yunnan, PR China. shilei@mail.kiz.ac.cn.|Yunnan Key Laboratory of Primate Biomedical Research, Kunming, 650000, China. shilei@mail.kiz.ac.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Road, Kunming, 650223, Yunnan, PR China. linqiang@mail.kiz.ac.cn.|Yunnan Key Laboratory of Primate Biomedical Research, Kunming, 650000, China. linqiang@mail.kiz.ac.cn.|Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100101, China. linqiang@mail.kiz.ac.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Road, Kunming, 650223, Yunnan, PR China. sub@mail.kiz.ac.cn.|Yunnan Key Laboratory of Primate Biomedical Research, Kunming, 650000, China. sub@mail.kiz.ac.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009929:Organ Size; D011323:Primates / Q000145:classification / Q000235:genetics; D011401:Promoter Regions, Genetic; D020218:Response Elements
chemical_list: D004967:Estrogens; D009419:Nerve Tissue Proteins