title: Uncovering novel reproductive defects in neurokinin B receptor null mice: closing the gap between mice and men.
abstract: Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3(-/-) mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, and fertility. Tacr3(-/-) mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3(-/-) males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3(-/-) females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3(-/-) females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3(-/-) females achieved fertility when mated. However, Tacr3(-/-) females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release.
authors.affiliation: Harvard Reproductive Sciences Center, Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Jasmine J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Caligioni
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
mesh_terms: D000818:Animals; D004971:Estrus / Q000378:metabolism / Q000502:physiology; D005260:Female; D005298:Fertility; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D018042:Receptors, Neurokinin-3 / Q000235:genetics*; D012098:Reproduction; D013737:Testis / Q000473:pathology; D013997:Time Factors
chemical_list: D018042:Receptors, Neurokinin-3; D007987:Gonadotropin-Releasing Hormone