LAUSR

Abstract Tachykinins (TACs) result from the differential processing of two genes in rodents, Tac1 (encoding substance P (SP) and neurokinin A (NKA)) and Tac2 (encoding NKB). TACs exert their effects in the hypothalamus by acting on different G protein-coupled receptors (GPCRs): NK1R, the receptor of SP, NK2R, the receptor of NKA, and NK3R, the receptor of NKB. We and others have documented a stimulatory role for all these tachykinins in the release of GnRH in the presence of physiological circulating levels of sex steroids. Important cross-reactivity between the TAC ligand-receptor systems has been documented and suggested as a possible cause for the reversal of hypogonadal NKB-signaling deficient patients. In order to test the possible redundancy in the TAC systems, we generated a mouse model of congenital removal of all TACs (Tac1KO/Tac2KO, aka TACKO). This model revealed a sexually dimorphic effect of TACs on puberty onset and fertility. TACKO male mice (n= 14) displayed delayed puberty onset compared with wildtype (WT) littermates, resembling Tac1KO and Tac2KO mice separately, but retained normal fertility. By contrast, TACKO females presented a slight delay in the timing of vaginal opening (VO) -a marker of puberty onset—, compared to controls, but none of the females (n=10) presented signs of first estrus within 30 days after VO, indicating a failure to undergo complete sexual maturation. This was supported by a profound reproductive impairment, as only 20% of the TACKO females that were mated with fertile WT males for 8 weeks delivered pups (and these litters presented a significantly reduced number of pups and significantly larger parturition latency than controls). To test the ability of TACKO females to mount a normal LH surge, a similar cohort of TACKO females (n = 5) was subjected to an LH surge inducing protocol, which evidenced the absence of a detectable preovulatory surge in KO mice. Overall, these data suggest a novel role for TACs as essential players in the induction of the preovulatory LH surge in females, through a redundant mechanism that is only evident in the absence of all TACs, but not in the absence of Tac1 or Tac2, separately. These data further suggest that while TACs participate in the timing of puberty onset in both sexes, they are dispensable for the tonic (pulsatile) release of GnRH/LH as evidenced by the normal fertile phenotype of male TACKO mice. Because preoptic area Kiss1 neurons do not coexpress TACs, these findings strongly support an additional role for caudal hypothalamic (arcuate and ventromedial nuclei) neurons in the control of ovulation. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.