ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice

Abstract

Abstract 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)α in KNDy cells, we thus generated Tac2Cre and Kiss1Cre knock-in mice and bred them onto the Esr1flox background to ablate ERα specifically in Tac2-expressing cells (ERαTac2KO mice) or all Kiss1 cells (ERαKiss1KO mice), respectively. Most ERα-expressing Tac2 neurons represent KNDy cells. Arcuate nucleus Kiss1 expression was elevated in ERαTac2KO and ERαKiss1KO females independent of gonadal hormones, whereas rostral hypothalamic Kiss1 expression was normal in ERαTac2KO but decreased in ERαKiss1KO females; this suggests that ERα in rostral Kiss1 cells is crucial for control of Kiss1 expression in these cells. Both ERαKiss1KO and ERαTac2KO females displayed early vaginal opening, early and persistent vaginal cornification, increased gonadotropins, uterine hypertrophy, and other evidence of estrogen excess. Thus, deletion of ERα in Tac2 neurons suffices to drive precocious gonadal hyperstimulation, demonstrating that ERα in Tac2 neurons typically restrains pubertal onset and hypothalamic reproductive drive.