Bliss Stuart P, Miller Andrew, Navratil Amy M, Xie Jianjun, McDonough Sean P, Fisher Patricia J, Landreth Gary E, Roberson Mark S
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Mol Endocrinol. 2009 Jul;23(7):1092-101. doi: 10.1210/me.2009-0030. Epub 2009 Apr 16.
Males and females require different patterns of pituitary gonadotropin secretion for fertility. The mechanisms underlying these gender-specific profiles of pituitary hormone production are unknown; however, they are fundamental to understanding the sexually dimorphic control of reproductive function at the molecular level. Several studies suggest that ERK1 and -2 are essential modulators of hypothalamic GnRH-mediated regulation of pituitary gonadotropin production and fertility. To test this hypothesis, we generated mice with a pituitary-specific depletion of ERK1 and 2 and examined a range of physiological parameters including fertility. We find that ERK signaling is required in females for ovulation and fertility, whereas male reproductive function is unaffected by this signaling deficiency. The effects of ERK pathway ablation on LH biosynthesis underlie this gender-specific phenotype, and the molecular mechanism involves a requirement for ERK-dependent up-regulation of the transcription factor Egr1, which is necessary for LHbeta expression. Together, these findings represent a significant advance in elucidating the molecular basis of gender-specific regulation of the hypothalamic-pituitary-gonadal axis and sexually dimorphic control of fertility.
男性和女性生育需要不同模式的垂体促性腺激素分泌。垂体激素产生的这些性别特异性特征背后的机制尚不清楚；然而，它们对于在分子水平上理解生殖功能的性别二态性控制至关重要。多项研究表明，ERK1和-2是下丘脑GnRH介导的垂体促性腺激素产生和生育调节的重要调节因子。为了验证这一假设，我们构建了ERK1和2垂体特异性缺失的小鼠，并检测了包括生育能力在内的一系列生理参数。我们发现，ERK信号在雌性小鼠排卵和生育中是必需的，而雄性生殖功能不受这种信号缺陷的影响。ERK通路缺失对LH生物合成的影响是这种性别特异性表型的基础，其分子机制涉及对转录因子Egr1的ERK依赖性上调的需求，而Egr1是LHβ表达所必需的。这些发现共同代表了在阐明下丘脑-垂体-性腺轴性别特异性调节和生育性别二态性控制的分子基础方面的重大进展。
