Absent Progesterone Signaling in Kisspeptin Neurons Disrupts the LH Surge and Impairs Fertility in Female Mice

被引:82
|
作者
Stephens, Shannon B. Z. [1 ]
Tolson, Kristen P. [1 ]
Rouse, Melvin L., Jr. [1 ]
Poling, Matthew C. [1 ]
Hashimoto-Partyka, Minako K. [2 ]
Mellon, Pamela L. [1 ]
Kauffman, Alexander S. [1 ]
机构
[1] Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA
[2] Univ Calif Los Angeles, Dept Mol Cellular & Dev Biol, Los Angeles, CA 90095 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
ESTROGEN POSITIVE FEEDBACK; LUTEINIZING-HORMONE SURGE; KISS1; GENE-EXPRESSION; SEXUAL-DIFFERENTIATION; GNRH NEURONS; RECEPTOR; BRAIN; ACTIVATION; MOUSE; ESTRADIOL;
D O I
10.1210/en.2015-1300
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estrogen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought to mediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone receptors and display enhanced neuronal activation during the LH surge. However, although estrogen regulation of kisspeptin neurons has been well studied, the role of progesterone signaling in regulating kisspeptin neurons is unknown. Here we tested whether progesterone action specifically in kisspeptin cells is essential for proper LH surge and fertility. We used Cre-lox technology to generate transgenic mice lacking progesterone receptors exclusively in kisspeptin cells (termed KissPRKOs). Male KissPRKOs displayed normal fertility and gonadotropin levels. In stark contrast, female KissPRKOs displayed earlier puberty onset and significant impairments in fertility, evidenced by fewer births and substantially reduced litter size. KissPRKOs also had fewer ovarian corpora lutea, suggesting impaired ovulation. To ascertain whether this reflects a defect in the ability to generate sex steroid-induced LH surges, females were exposed to an estradiol-positive feedback paradigm. Unlike control females, which displayed robust LH surges, KissPRKO females did not generate notable LH surges and expressed significantly blunted cfos induction in anterior ventral periventricular nucleus kisspeptin neurons, indicating that progesterone receptor signaling in kisspeptin neurons is required for normal kisspeptin neuronal activation and LH surges during positive feedback. Our novel findings demonstrate that progesterone signaling specifically in kisspeptin cells is essential for the positive feedback induction of normal LH surges, ovulation, and normal fertility in females.
引用
收藏
页码:3091 / 3097
页数:7
相关论文
共 50 条
  • [1] Loss of Fertility in the Absence of Progesterone Receptor Expression in Kisspeptin Neurons of Female Mice
    Gal, Arnon
    Lin, Po-Ching
    Cacioppo, Joseph A.
    Hannon, Patrick R.
    Mahoney, Megan M.
    Wolfe, Andrew
    Fernandez-Valdivia, Rodrigo
    Lydon, John P.
    Elias, Carol F.
    Ko, CheMyong
    PLOS ONE, 2016, 11 (07):
  • [2] Progesterone Receptors in AVPV Kisspeptin Neurons Are Sufficient for Positive Feedback Induction of the LH Surge
    Mohr, Margaret A.
    Esparza, Lourdes A.
    Steffen, Paige
    Micevych, Paul E.
    Kauffman, Alexander S.
    ENDOCRINOLOGY, 2021, 162 (11)
  • [3] Dynorphin and GABAA Receptor Signaling Contribute to Progesterone's Inhibition of the LH Surge in Female Mice
    Liu, Yali
    Li, Xiaofeng
    Ivanova, Deyana
    Lass, Geffen
    He, Wen
    Chen, Qiuju
    Yu, Sha
    Wang, Yun
    Long, Hui
    Wang, Li
    Lyu, Qifeng
    Kuang, Yanping
    O'Byrne, Kevin T.
    ENDOCRINOLOGY, 2020, 161 (05)
  • [4] Acute Suppression of LH Secretion by Prolactin in Female Mice Is Mediated by Kisspeptin Neurons in the Arcuate Nucleus
    Brown, Rosemary S. E.
    Aung, Zin Khant
    Phillipps, Hollian R.
    Barad, Zsuzsanna
    Lein, Hsin-Jui
    Boehm, Ulrich
    Szawka, Raphael E.
    Grattan, David R.
    ENDOCRINOLOGY, 2019, 160 (05) : 1323 - 1332
  • [5] Hindbrain Adenosine 5-Triphosphate (ATP)-Purinergic Signaling Triggers LH Surge and Ovulation via Activation of AVPV Kisspeptin Neurons in Rats
    Inoue, Naoko
    Hazim, Safiullah
    Tsuchida, Hitomi
    Dohi, Yuri
    Ishigaki, Ren
    Takahashi, Ai
    Otsuka, Yuki
    Yamada, Koki
    Uenoyama, Yoshihisa
    Tsukamura, Hiroko
    JOURNAL OF NEUROSCIENCE, 2023, 43 (12) : 2140 - 2152
  • [6] Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons
    Mayer, Christian
    Acosta-Martinez, Maricedes
    Dubois, Sharon L.
    Wolfe, Andrew
    Radovick, Sally
    Boehm, Ulrich
    Levine, Jon E.
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (52) : 22693 - 22698
  • [7] Neonatal Exposure to 17α-Ethinyl Estradiol Affects Kisspeptin Expression and LH-Surge Level in Female Rats
    Usuda, Kento
    Nagaoka, Kentaro
    Nozawa, Kaori
    Zhang, Haolin
    Taya, Kazuyoshi
    Yoshida, Midori
    Watanabe, Gen
    JOURNAL OF VETERINARY MEDICAL SCIENCE, 2014, 76 (08) : 1105 - 1110
  • [8] Glutamatergic Input From Arcuate Nucleus Kiss1 Neurons to Preoptic Kiss1 Neurons Is Required for LH Surge in Female Mice
    Qiu, Jian
    Talbi, Rajae
    Bosch, Martha A.
    Medve, Elizabeth
    Zweifel, Larry S.
    Ronnekleiv, Oline K.
    Navarro, Victor M.
    Kelly, Martin J.
    ENDOCRINOLOGY, 2025, 166 (02)
  • [9] The molecular phenotype of kisspeptin neurons in the medial amygdala of female mice
    Hatcher, Katherine M.
    Costanza, Leah
    Kauffman, Alexander S.
    Stephens, Shannon B. Z.
    FRONTIERS IN ENDOCRINOLOGY, 2023, 14
  • [10] Vasoactive Intestinal Peptide Modulation of the Steroid-Induced LH Surge Involves Kisspeptin Signaling in Young but Not in Middle-Aged Female Rats
    Kauffman, Alexander S.
    Sun, Yan
    Kim, Joshua
    Khan, Azim R.
    Shu, Jun
    Neal-Perry, Genevieve
    ENDOCRINOLOGY, 2014, 155 (06) : 2222 - 2232