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TACkling NKB's role in puberty.

Over the past decade, scientists have unveiled the central importance of kisspeptin (Kiss1) signaling in the brain for control of GnRH secretion (1). However, neurokinin B (NKB), a member of the tachykinin peptide family, enjoys prominence as a Kiss1 cotransmitter and harbors secrets untold. NKB, along with Kiss1 and dynorphin, is synthesized and released by so-called “KNDy” neurons located within the arcuate nucleus of the hypothalamus (a homologue of the infundibular nucleus in primates) (2–5). NKB is encoded by the TAC3 gene in humans and the Tac2 gene in mice; the NKB receptor (NK3R) is encoded by the TACR3 gene in humans and the Tacr3 gene in mice. Kiss1 reigns as the most potent secretagogue for GnRH and LH secretion, and KNDy neurons serve as the nodal point for sex steroiddependent feedback control of GnRH and LH secretion in both sexes (6, 7). Dynorphin suppresses GnRH release by inhibiting KNDy neuronal activity and may be responsible for interrupting GnRH secretion during the interpulse intervals of Kiss1/GnRH secretion (8, 9). In contrast, NKB stimulates KNDy neuronal activity and thereby indirectly triggers GnRH (and LH) secretion (8, 10–12). Kiss1 and NKB play key roles in modulating GnRH secretion and, thus, reproductive function in both male and female animals (13– 16). Indeed, humans with impaired TAC3 and TACR3 signaling (as a result of mutations) exhibit hypogonadotropic hypogonadism, reminiscent of patients with KISS1R mutations (17–20). However, the observation of a “reversal” phenomenon in which TAC3/TAC3R-impaired hypogonadotropic hypogonadism patients regain hypothalamicpituitary-gonadal function after treatment disputes the notion that NKB signaling is a prerequisite for sustaining normal reproduction (21–23). Studies of NKB signaling in mice have generated intriguing, albeit paradoxical, findings. In 2012, Seminara and coworkers (24) demonstrated that mice lacking the gene encoding NK3R (Tacr3-null) exhibit significant reproductive impairment, despite being technically “fertile” as adults. In an editorial commentary on this article, we noted incongruities between the effects of genetically targeted NKB receptor ablations in mice and TACR3 mutations in humans, and we posed several questions. Why do humans bearing a TACR3 mutation exhibit infertility (notwithstanding phenotypic reversal after treatment), whereas Tacr3-null mice enter puberty normally and exhibit normal fertility? Why do humans with TACR3 mutations exhibit delayed puberty, but mice lacking Tacr3 exhibit no reproductive impairment until adulthood? To address these and other questions, the Seminara team broadened its approach and began searching for a better model of disrupted NKB signaling. In the current issue of Endocrinology, True et al (25) present a detailed analysis of the reproductive phenotypes of male and female mice that are homozygous for mutations in Tac2. On the one hand, male Tac2 / mice progress normally through puberty and become fertile in adulthood. To the contrary, female Tac2 / mice exhibit delayed sexual maturation, with abnormal cycling and reduced fertility in adulthood. However, by postnatal day 94, Tac2 / females recover estrous cyclicity and exhibit normal physiological levels of LH and FSH. The finding of delayed puberty in female Tac2 / mice contrasts with female Tacr3 / mice, which show normal timing of puberty. However, the reproductive effects of Tac2 ablation in female mice closely recapitulate the reproductive deficits, and cycle recovery, observed in women with disrupted NKB signaling. These observations support the argument of True et al (25) that NKB is necessary for proper timing of sexual maturation, but not for sustaining normal adult reproductive function once it begins. Curiously, the re-