Reproduction is a complex process governed by the interplay of central and peripheral factors. The major signal controlling reproduction is the hypothalamic GnRH, responsible of the release of pituitary gonadotropins that drive gonadal function. Thus, diverse conditions disturbing reproductive function are related to defects in factors and/or routes involved in the control of GnRH release. As an example, kisspeptins (encoded by the Kiss1 gene) and their receptor GPR54 have emerged as essential gatekeepers of GnRH neurons, and disruption of kisspeptin/GPR54 signaling lead to hypogonadotropic hypogonadism (HH) in humans and mice (one of the most relevant breakthroughs in contemporary Neuroendocrinology). However, the mechanisms that regulate the hypothalamic Kiss1 system remain partially unknown. Recently, prokineticin-2 (PK2) and its receptor (PKR2) have been involved in the control of reproductive maturation and/or function, as loss-of-function mutations in either the receptor or the ligand lead to HH. Considering that PK2 was originally described as a circadian pacemaker from the suprachiasmatic nucleus (SCN; the central translator of the photoperiodic status to the organism) and that key aspects of reproductive function (such as the preovulatory LH surge; responsible for ovulation) are exquisitely timed, the AIM of this project is to explore the basis for the regulatory actions of the PK2/PK2R system on GnRH neurons, and to evaluate whether Kiss1 neurons operate as essential relay for such a transmission. To accomplish this goal, a combination of gene expression (RT-PCR, in situ hybridization), protein (ICC) assays and functional (hormonal) tests, will be implemented in wild-type and genetically-modified mice. Implementation of this project will broaden our basic knowledge on the physiological mechanisms governing reproduction in mammals; knowledge which might be translatable to rational therapeutic strategies for the control (promotion or blockade) of fertility.
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Funding SchemeMC-IOF - International Outgoing Fellowships (IOF)
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