title: ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice.
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 Tac2(Cre) and Kiss1(Cre) knock-in mice and bred them onto the Esr1(flox) background to ablate ERα specifically in Tac2-expressing cells (ERα(Tac2)KO mice) or all Kiss1 cells (ERα(Kiss1)KO mice), respectively. Most ERα-expressing Tac2 neurons represent KNDy cells. Arcuate nucleus Kiss1 expression was elevated in ERα(Tac2)KO and ERα(Kiss1)KO females independent of gonadal hormones, whereas rostral hypothalamic Kiss1 expression was normal in ERα(Tac2)KO but decreased in ERα(Kiss1)KO females; this suggests that ERα in rostral Kiss1 cells is crucial for control of Kiss1 expression in these cells. Both ERα(Kiss1)KO and ERα(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 ERα in Tac2 neurons suffices to drive precocious gonadal hyperstimulation, demonstrating that ERα in Tac2 neurons typically restrains pubertal onset and hypothalamic reproductive drive.
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Megan L
authors: ML
authors: Greenwald-Yarnell
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Courtney
authors: C
authors: Marsh
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Margaret B
authors: MB
authors: Allison
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Christa M
authors: CM
authors: Patterson
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Chelsea
authors: C
authors: Kasper
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Alexander
authors: A
authors: MacKenzie
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Roberta
authors: R
authors: Cravo
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Carol F
authors: CF
authors: Elias
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Suzanne M
authors: SM
authors: Moenter
authors: Neuroscience Graduate Program (M.L.G.-Y., S.M.M., M.G.M.); Division of Metabolism, Endocrinology and Diabetes (M.L.G.-Y., M.B.A., C.M.P., C.K., A.M., S.M.M., M.G.M.), Department of Internal Medicine; and Departments of Obstetrics and Gynecology (C.M., C.F.E., S.M.M.) and Molecular and Integrative Physiology (M.B.A., R.C., C.F.E., S.M.M., M.G.M.), University of Michigan, Ann Arbor, Michigan 48109.
authors: Martin G
authors: MG
authors: Myers
mesh_terms: D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006062:Gonadotropins / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism*; D010052:Ovariectomy; D010053:Ovary / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation / Q000235:genetics / Q000502:physiology*; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014599:Uterus / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D006062:Gonadotropins; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; D004958:Estradiol; D004399:Dynorphins