Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility.
The mechanisms through which estrogen regulates gonadotropin-releasing hormone (GnRH) neurons to control mammalian ovulation are unknown. We found that estrogen positive feedback to generate the preovulatory gonadotropin surge was normal in estrogen receptor beta knockout (ERbeta) mutant mice, but absent in ERalpha mutant mice. An ERalpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ERalpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERalpha mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ERalpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ERalpha-expressing neurons innervating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate that ovulation is driven by estrogen actions upon ERalpha-expressing neuronal afferents to GnRH neurons.
Wintermantel
Tim M
TM
Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Campbell
Rebecca E
RE
Porteous
Robert
R
Bock
Dagmar
D
Gröne
Hermann-Josef
HJ
Todman
Martin G
MG
Korach
Kenneth S
KS
Greiner
Erich
E
Pérez
Cristian A
CA
Schütz
Günther
G
Herbison
Allan E
AE
D000818:Animals; D045166:Estradiol Congeners / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000819:agonists / Q000378:metabolism*; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D011558:Herpesvirus 1, Suid / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D007033:Hypothalamus, Middle / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*
D045166:Estradiol Congeners; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone