The role of kisspeptin and RFRP-3 in the neuroendocrine control of female reproduction

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Project Summary Successful female reproduction requires the precise temporal coordination of numerous neuroendocrine events by a master circadian pacemaker in the suprachiasmatic nucleus (SCN). Across species, including humans, disruptions to circadian timing result in pronounced abnormalities in the estrous/menstrual cycle, reductions in fertility, and increased miscarriage rates. Our findings to date provide evidence for a network of ovulatory control in which the SCN temporally coordinates the activity of two, key neuropeptidergic systems with opposing actions, the RFamide-related peptide-3 (RFRP-3, the mammalian ortholog of avian gonadotropin-inhibitory hormone) and kisspeptin systems. Across mammalian species, RFRP-3 and kisspeptin are key inhibitory and stimulatory regulators of the reproductive axis, respectively. Despite the well-established role for these neuropeptides in mammalian reproduction, as well as the knowledge that the circadian timing system is a crucial regulator of the female reproductive axis, the specific means by which interactions among these systems appropriately coordinate the timing of neuroendocrine events necessary for ovulation remain unspecified. To understand how elements of this network synergize to produce the coordinated output to the gonadotropin-releasing hormone (GnRH) system required for ovulation, the present proposal uses transgenic mouse models, in combination with cell-specific viral approaches, to elucidate the cellular mechanisms and neurochemical signaling pathways by which the circadian clockwork interfaces with the RFRP-3 and Kp systems. Specifically, the present proposal will: 1) identify the neurochemical signaling pathways by which the SCN communicates with the RFRP-3 and kisspeptin systems, 2) examine the functional contribution of identified pathways systematically, and with cell-specific precision, and 3) determine the functional significance of autonomous, neuroendocrine-cell circadian timekeeping in this network of control through cell-phenotype-specific knockdown of essential clock genes. The proposed work not only addresses a classic question in reproductive biology, but also has the potential for substantial translational impact in the development of safe/effective contraception, as well as the treatment of a host of reproductive disorders in humans, including precocious and delayed puberty, infertility, and polycystic ovarian syndrome.