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Estrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates.

Shi L, Lin Q, Su B - BMC Evol. Biol. (2015)

Bottom Line: 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.Brain size dimorphism among certain primates, including humans, is likely regulated by estrogen through its sex-dependent suppression of brain size genes during development.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Identification of half EREs in the MCPH gene promoter sequences. The half EREs were mapped based on the gene’s translational start site
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Fig1: Identification of half EREs in the MCPH gene promoter sequences. The half EREs were mapped based on the gene’s translational start site

Mentions: To determine whether estradiol could regulate the seven currently known microcephaly genes (ASPM, CENPJ, CEP152, CDK5RAP2, MCPH1, STIL and WDR62), we conducted a search of the potential ERE (estrogen response element) sites in gene promoter regions. Four genes (ASPM, CDK5RAP2, MCPH1 and WDR62) contain predicted half ERE sites (TGACC or GGTCA) in their promoters (Fig. 1) [33, 34]. In total, there are two predicted half ERE sites in ASPM (Fig. 1), six in CDK5RAP2 (Fig. 1), three in MCPH1 (Fig. 1) and two in WDR62 (Fig. 1). Sequence alignments of the promoter regions of representative primate species and mouse indicated that the predicted half ERE sites are, in general, conserved among human and nonhuman primates (Fig. 1), implying functional constraints on these half ERE sites. However, for ASPM and MCPH1, 4 out of the 5 half ERE sites are not conserved in marmosets (Fig. 1).Fig. 1


Estrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates.

Shi L, Lin Q, Su B - BMC Evol. Biol. (2015)

Identification of half EREs in the MCPH gene promoter sequences. The half EREs were mapped based on the gene’s translational start site
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487212&req=5

Fig1: Identification of half EREs in the MCPH gene promoter sequences. The half EREs were mapped based on the gene’s translational start site
Mentions: To determine whether estradiol could regulate the seven currently known microcephaly genes (ASPM, CENPJ, CEP152, CDK5RAP2, MCPH1, STIL and WDR62), we conducted a search of the potential ERE (estrogen response element) sites in gene promoter regions. Four genes (ASPM, CDK5RAP2, MCPH1 and WDR62) contain predicted half ERE sites (TGACC or GGTCA) in their promoters (Fig. 1) [33, 34]. In total, there are two predicted half ERE sites in ASPM (Fig. 1), six in CDK5RAP2 (Fig. 1), three in MCPH1 (Fig. 1) and two in WDR62 (Fig. 1). Sequence alignments of the promoter regions of representative primate species and mouse indicated that the predicted half ERE sites are, in general, conserved among human and nonhuman primates (Fig. 1), implying functional constraints on these half ERE sites. However, for ASPM and MCPH1, 4 out of the 5 half ERE sites are not conserved in marmosets (Fig. 1).Fig. 1

Bottom Line: 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.Brain size dimorphism among certain primates, including humans, is likely regulated by estrogen through its sex-dependent suppression of brain size genes during development.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus