MON-149 Dissecting The Roles Of Kiss1Avpv Neurons In The Control Of Puberty, LH Secretion And Ovulation By Functional Genomics

Abstract Disclosure: J. Garcia-Vera: None. F. Ruiz-Pino: None. A. Barroso-Romero: None. C. Torres-Granados: None. S. Daza-Dueñas: None. S. Leon: None. F. Gaytan: None. D. Garcia-Galiano: None. M. Tena-Sempere: None. Kisspeptins (Kp), encoded by Kiss1 gene, play indispensable roles in the integral control of reproduction, via discrete populations of Kiss1 neurons, mainly located in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) of the hypothalamus. While the role of Kiss1ARC neurons, as key component of the GnRH/LH pulse generator, is well defined, Kiss1AVPV neurons are suggested to contribute to the preovulatory surge of gonadotropins triggering ovulation; yet, more granular dissection of the actual roles of Kiss1AVPV neurons in different facets of reproductive function is still missing. We report herein a comprehensive series of analyses of the function of Kiss1AVPV neurons by combining virogenetic approaches with the generation of a congenital Kiss1 KO model to induce conditional inactivation of Kiss1 expression in the AVPV. Histochemical analyses documented that a vast majority of Kiss1AVPV neurons co-express tyrosine hydroxylase (TH), and virtually all are estrogen sensitive. Thus, we generated of a TH-specific Kiss1 KO (TyKKO) mouse line, by crossing Th-Cre and Kiss1fl/fl mice, which displays blunted Kiss1 but preserved Th mRNA expression in the AVPV. TyKKO females, but not males, showed delayed pubertal development, with deferred vaginal opening and first estrus, and displayed longer and more irregular estrous cycles in adulthood. A protocol of estrogen-primed LH surge failed to induce the prototypical (preovulatory-like) rise of LH levels in TyKKO females, despite successful induction in controls. In good agreement, TH-specific Kiss1 KO resulted in anovulation. To control for potential developmental defects, inactivation of Kiss1 expression in the AVPV was carried out also in adult Kiss1fl/fl female mice, by bilateral injection of viral vectors expressing Cre recombinase. Effective ablation was documented by RNAscope and qPCR of AVPV micro-punches. In line with TyKKO data, Kiss1fl/fl females injected in the AVPV with viral Cre displayed disrupted estrous cyclicity and lack of estrogen-induced LH surges, together with halted ovulation. Interestingly, adult females with virogenetic inactivation of AVPV Kiss1 seemingly maintained LH pulsatility, likely denoting preservation of Kiss1ARC neuronal function. In sum, our data dissect out the roles of Kiss1AVPV neurons, that participate in the control of female puberty and are indispensable for the neuro-endocrine trigger of preovulatory LH surges and ovulation, but not for LH pulsatility. Presentation: Monday, July 14, 2025