OR04-2 Delayed sexual maturation in mice lacking neurokinin B mirrors the phenotype of human patients with mutations in the neurokinin B pathway

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR04-GnRH & Gonadotroph Biology & Signaling
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 11:45 AM
Room 135 (Moscone Center)
Sayeda Nasrin Alam*, Cadence True, Margaret Flynn Lippincott, Yee-Ming Chan and Stephanie Beth Seminara*
Massachusetts General Hospital, Boston, MA
Humans with mutations in the neurokinin B (NKB) signaling pathway (TAC3 and TACR3) have hypogonadotropic hypogonadism although these patients frequently demonstrate reversal of their GnRH-deficient state. Tacr3-/- mice exhibit normal timing of sexual maturation but have abnormal estrous cycling and subfertility. As Tac2-/- mice (neurokinin B deficient) have yet to be described, we sought to characterize the reproductive phenotype of these animals, and hypothesized that they would be less severely affected than their receptor counterparts.Targeted deletion of all exons of Tac2 was achieved by homologous recombination on a C57Bl/6/129Sv background strain by the Texas A&M Institute for Genomic Medicine. Mice were weighed and examined daily from P21-P36 for evidence of sexual maturation. Daily vaginal smears were done from day of vaginal opening to P90.

The Tac2 deficient state was confirmed by an absence of NKB immunoreactivity (Novus Biological, 1:1000) in the arcuate nucleus. Compared to controls, Tac2-/- females demonstrated delayed vaginal opening (P 25.1 ± 0.6 vs. P 27.4 ± 0.9; p<0.05) and time to first estrus (P 31.3 ± 1.3 vs. P 41.9 ± 2.7; p<0.01). In addition, Tac2-/- females had significantly longer cycle lengths (4.4 ± 0.2 days vs. 12.4 ± 0.9 days; p<0.001). Despite the abnormalities in estrous cyclicity, all Tac2-/- females achieved pregnancy when placed in a cage with WT or Tac2-/- males. Although the time to preputial separation, anogenital distance and testicular weight were all suggestive of an abnormal reproductive phenotype in  Tac2-/- males, these differences were not statistically different from littermate controls.   

 Tac2-/- females have delayed time to vaginal opening, delayed first estrous, and abnormal cycling compared to WT littermates, but seemingly robust fertility. Whereas both Tac2-/- and Tacr3-/- mice have abnormal estrus cycling, only Tac2-/- mice have significant delays in sexual maturation.  Though subtle background differences between different B6/129 hybrid lines cannot be excluded, this unexpected difference in the timing of sexual maturation between Tac2-/- and Tacr3-/- female animals suggests that neurokinin B may signal through multiple tachykinin receptors to modulate the hypothalamic-pituitary-gonadal axis. Tac2-/- mice have parallels to humans with reversible hypogonadotropism, with defects in sexual maturation but recovery of reproductive function and fertility in adulthood.

Nothing to Disclose: SNA, CT, MFL, YMC, SBS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: HD028138-22