Limits...
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.

Show MeSH

Related in: MedlinePlus

E2 suppresses the promoter activities of MCPH genes in SK-N-SH cells. a-d Quantification of promoter activity of ASPM, CDK5RAP2, MCPH1 and WDR62 using luciferase reporter gene assay. The SK-N-SH cells (derived from human neuroblastoma) were transiently transfected with vector containing human ERα
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: E2 suppresses the promoter activities of MCPH genes in SK-N-SH cells. a-d Quantification of promoter activity of ASPM, CDK5RAP2, MCPH1 and WDR62 using luciferase reporter gene assay. The SK-N-SH cells (derived from human neuroblastoma) were transiently transfected with vector containing human ERα

Mentions: Furthermore, we used a neural cell line (the SK-N-SH cell line derived from human neuroblastoma) and tested all four primate species including marmosets. We observed a similar pattern, in which the repression effects are conserved across humans, chimpanzees and macaques that are known to exhibit sexual dimorphism (Fig. 4). In marmosets, WDR62 and CDK5RAP2 also showed the repression effects (Fig. 4b and d), but ASPM and MCPH1 did not (Fig. 4a and c) because their half ERE sites are not conserved in marmosets (Fig. 1). This observation is consistent with the fact that marmosets do not have brain sexual dimorphism [5].Fig. 4


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

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

E2 suppresses the promoter activities of MCPH genes in SK-N-SH cells. a-d Quantification of promoter activity of ASPM, CDK5RAP2, MCPH1 and WDR62 using luciferase reporter gene assay. The SK-N-SH cells (derived from human neuroblastoma) were transiently transfected with vector containing human ERα
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: E2 suppresses the promoter activities of MCPH genes in SK-N-SH cells. a-d Quantification of promoter activity of ASPM, CDK5RAP2, MCPH1 and WDR62 using luciferase reporter gene assay. The SK-N-SH cells (derived from human neuroblastoma) were transiently transfected with vector containing human ERα
Mentions: Furthermore, we used a neural cell line (the SK-N-SH cell line derived from human neuroblastoma) and tested all four primate species including marmosets. We observed a similar pattern, in which the repression effects are conserved across humans, chimpanzees and macaques that are known to exhibit sexual dimorphism (Fig. 4). In marmosets, WDR62 and CDK5RAP2 also showed the repression effects (Fig. 4b and d), but ASPM and MCPH1 did not (Fig. 4a and c) because their half ERE sites are not conserved in marmosets (Fig. 1). This observation is consistent with the fact that marmosets do not have brain sexual dimorphism [5].Fig. 4

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