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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $426,550

## Abstract

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.

## Key facts

- **NIH application ID:** 10134388
- **Project number:** 5R01HD050470-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Lance J Kriegsfeld
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,550
- **Award type:** 5
- **Project period:** 2007-03-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134388

## Citation

> US National Institutes of Health, RePORTER application 10134388, The role of kisspeptin and RFRP-3 in the neuroendocrine control of female reproduction (5R01HD050470-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134388. Licensed CC0.

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