ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice

A variety of data suggest that estrogen action on kisspeptin (Kiss1)-containing arcuate nucleus neurons (which coexpress Kiss1, neurokinin B (the product of Tac2) and dynorphin (KNDy) neurons restrains reproductive onset and function, but roles for estrogen action in these Kiss1 neurons relative to a distinct population of rostral hypothalamic Kiss1 neurons (which does not express Tac2 or dynorphin) have not been directly tested. To test the role for estrogen receptor (ER) alpha in KNDy cells, we thus generated Tac2(Cre) and Kiss1(Cre) knock-in mice and bred them onto the Esr1(flox) background to ablate ER alpha specifically in Tac2-expressing cells (ER alpha(KO)-K-Tac2 mice) or all Kiss1 cells (ER alpha(KO)-K-Kiss1 mice), respectively. Most ER alpha-expressing Tac2 neurons represent KNDy cells. Arcuate nucleus Kiss1 expression was elevated in ER alpha(KO)-K-Tac2 and ER alpha(KO)-K-Kiss1 females independent of gonadal hormones, whereas rostral hypothalamic Kiss1 expression was normal in ER alpha(KO)-K-Tac2 but decreased in ER alpha(KO)-K-Kiss1 females; this suggests that ER alpha in rostral Kiss1 cells is crucial for control of Kiss1 expression in these cells. Both ER alpha(KO)-K-Kiss1 and ER alpha(KO)-K-Tac2 females displayed early vaginal opening, early and persistent vaginal cornification, increased gonadotropins, uterine hypertrophy, and other evidence of estrogen excess. Thus, deletion of ER alpha in Tac2 neurons suffices to drive precocious gonadal hyperstimulation, demonstrating that ER alpha in Tac2 neurons typically restrains pubertal onset and hypothalamic reproductive drive.