Quinnies Kayla M, Bonthuis Paul J, Harris Erin P, Shetty Savera Rj, Rissman Emilie F
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908 USA ; Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908 USA.
Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132-3401 USA.
Biol Sex Differ. 2015 Apr 28;6:8. doi: 10.1186/s13293-015-0026-x. eCollection 2015.
Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum.
We used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17β-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons.
Estradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate.
Sex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.
垂体生长激素（GH）的性别差异已有充分记录，且与成熟和生长过程相互协调。GH及其受体也在大脑中产生，它们可能影响认知功能和突触可塑性，并且雌二醇在大鼠海马体中产生GH性别差异。在小鼠中，循环雌二醇会增加雌性而非雄性内侧视前区（mPOA）的Gh mRNA；因此，其他因素调节大脑中GH的性别二态性表达。因此，我们假设性染色体与雌二醇相互作用以促进GH的性别差异。在此，我们评估了雌二醇和性染色体组成对三个大脑大区域（海马体、下丘脑和小脑）中Gh mRNA水平的影响。
我们使用了四核心基因型（FCG）小鼠，其将性染色体和性腺性别的影响解耦。FCG模型缺失Y染色体上的性别决定区域（Sry），并在常染色体上转基因插入Sry。成年FCG小鼠接受性腺切除，并给予空白硅橡胶植入物或含有17β-雌二醇的植入物。GH蛋白和mRNA的显著差异归因于雌二醇替代、性腺性别、性染色体组成及其相互作用，通过方差分析和计划比较进行评估。
无论性染色体组成或性腺性别如何，雌二醇都会增加小脑和海马体中的Gh mRNA。相比之下，在下丘脑中，雌性的Gh mRNA高于雄性，且XY雌性的Gh mRNA多于XY雄性和XX雌性。GH蛋白也观察到相同模式。由于下丘脑中Gh mRNA的差异未重复先前使用其他小鼠模型以及来自mPOA或弓状核组织的研究，我们检查了下丘脑一个亚区弓状核中的GH蛋白。与先前报告一样，与整个下丘脑不同，性染色体组成效应表明XX小鼠在弓状核中的GH比XY小鼠更多。
性染色体组成在部分而非所有脑区调节GH，并且在下丘脑中，性染色体对GH具有细胞特异性作用。因此，性染色体组成和雌二醇都对大脑中GH的性别差异有影响。
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