Tachykinin Signaling Is Required for Induction of the Preovulatory Luteinizing Hormone Surge and Normal Luteinizing Hormone Pulses

Abstract

Tachykinins (neurokinin A [NKA], neurokinin B [NKB], and substance P [SP]) are important components of the neuroendocrine control of reproduction by direct stimulation of Kiss1 neurons to control GnRH pulsatility, which is essential for reproduction. Despite this role of tachykinins in successful reproduction, knockout (KO) mice for <i>Tac1</i> (NKA/SP) and <i>Tac2</i> (NKB) genes are fertile, resembling the phenotype of human patients bearing NKB signaling mutations, who often reverse their hypogonadal phenotype. This suggests the existence of compensatory mechanisms among the different tachykinin ligand-receptor systems to maintain reproduction in the absence of one of them. In order to test this hypothesis, we generated complete tachykinin-deficient mice (<i>Tac1/Tac2</i>KO). Male mice displayed delayed puberty onset and decreased luteinizing hormone (LH) pulsatility (frequency and amplitude of LH pulses) but preserved fertility. However, females did not show signs of puberty onset (first estrus) within 45 days after vaginal opening, they displayed a low frequency (but normal amplitude) of LH pulses, and 80% of them remained infertile. Further evaluation identified a complete absence of the preovulatory LH surge in <i>Tac1/Tac2</i>KO females as well as in wild-type females treated with NKB or SP receptor antagonists. These data confirmed a fundamental role of tachykinins in the timing of puberty onset and LH pulsatility and uncovered a role of tachykinin signaling in facilitation of the preovulatory LH surge. Overall, these findings indicate that tachykinin signaling plays a dominant role in the control of ovulation, with potential implications as a pathogenic mechanism and a therapeutic target to improve reproductive outcomes in women with ovulation impairments.

Congenital ablation of Tacr2 reveals overlapping and redundant roles of NK2R signaling in the control of reproductive axis

“…This is in line with the preserved fertility of Tacr1 À/À mice (34), whereas Tacr3 À/À females were subfertile (28). In contrast, individual or compound ablation of the genes encoding the TAC ligands Tac1 and Tac2 resulted in subfertility, with the greatest perturbation being observed in Tac1/Tac2 null mice, which displayed infertility in 80% of the females (30). Preservation of fertility in mice lacking NK2R signaling was not seemingly attained by developmental compensation in our congenital KO model, as suggested by the conserved hypothalamic expression of key central elements of the reproductive axis, such as the genes encoding NKB, NK1R and NK3R, Kiss1, dynorphin, and GnRH.…”

“…This suggests a greater physiological relevance of NK2R signaling in the control of the female (vs. male) gonadotropic axis. In good agreement, the reproductive impact of individual or combined Tac1 and Tac2 ablation was higher in females (27,30,32), suggesting that the female reproductive axis is more sensitive to alterations in TAC signaling. Generation of novel murine models, with combined ablation of Tacr2 and Tacr1 and/or Tacr3, may help to further expose the degree of redundancy and compensation among the different TAC signaling pathways.…”

“…This is further supported by the fact that LH responses to the NK2R agonist could be totally blocked in Tacr2 À/À males pretreated with the pharmacological antagonist of NK3R. In the same vein, the phenotypic impact of genetic ablation of Tac1, encoding SP and NKA, has been recently shown to be augmented by the concomitant elimination of Tac2, encoding NKB (30). In any event, it is interesting to note that the impact of Tacr2 elimination on LH secretory responses to the NKA agonist was higher in females, suggesting that the degree of redundancy and compensation among the TAC pathways is lower than in males.…”

“…As a plausible interpretation, it has been proposed that, due to some degree of redundancy among the TAC pathways, SP/NK1R and/or NKA/NK2R signaling may compensate for the congenital absence of NKB actions, thereby preserving fertility in mice and permitting reversal of the hypogonadal state in humans, with genetic inactivation of the NKB pathway. This redundancy has been recently documented by phenotypic analyses on double Tac1/Tac2 KO mice, which displayed more profound reproductive defects than mice lacking one of the two Tac genes (30).…”

“…Our current data set expands those previous observations and demonstrates normal timing of puberty in Tacr2 À/À mice of either sex. Interestingly, ablation of Tac1 or combined elimination of Tac1/Tac2 did cause overt alterations of puberty in male and female mice (30), suggesting that the joint absence of several TACs is needed to overtly perturb puberty onset in rodents of both sexes. The fact that individual elimination of Tacr3 or Tacr2 did not alter pubertal timing in mice further emphasizes the functional redundancy of the TAC system also in terms of pubertal control; a contention that might be confirmed by compound ablation of all TAC receptors in future studies.…”