ER[alpha] 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 super(Cre) and Kiss1 super(Cre) knock-in mice and bred them onto the Esr1 super(flox) background to ablate ER[alpha] specifically in Tac2-expressing cells (ER[alpha] super(Tac2) KO mice) or all Kiss1 cells (ER[alpha] super(Kiss1) KO mice), respectively. Most ER[alpha]-expressing Tac2 neurons represent KNDy cells. Arcuate nucleus Kiss1 expression was elevated in ER[alpha] super(Tac2) KO and ER[alpha] super(Kiss1) KO females independent of gonadal hormones, whereas rostral hypothalamic Kiss1 expression was normal in ER[alpha] super(Tac2) KO but decreased in ER[alpha] super(Kiss1) KO females; this suggests that ER[alpha] in rostral Kiss1 cells is crucial for control of Kiss1 expression in these cells. Both ER[alpha] super(Kiss1) KO and ER[alpha] super(Tac2) KO 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.