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ERK Signaling in the Pituitary Is Required for Female But Not Male Fertility

Department of Biomedical Sciences (S.P.B., A.M., A.M.N., J.X., S.P.M., P.J.F., M.S.R.), College of Veterinary Medicine, Cornell University, Ithaca, New York 14853; and Department of Neurosciences (G.E.L.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Dr. Mark S. Roberson, Department of Biomedical Sciences, T4-018 Veterinary Research Tower, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853. E-mail: msr14{at}cornell.edu.

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 LHβ 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.

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