Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?
The activins were discovered and named based on their abilities to stimulate FSH secretion and FSHβ (Fshb) subunit expression by pituitary gonadotrope cells. According to subsequent in vitro observations, activins also stimulate the transcription of the GnRH receptor (Gnrhr) and the activin antagonist, follistatin (Fst). Thus, not only do activins stimulate FSH directly, they have the potential to regulate both FSH and LH indirectly by modulating gonadotrope sensitivity to hypothalamic GnRH. Moreover, activins may negatively regulate their own actions by stimulating the production of one of their principal antagonists. Here, we describe our current understanding of the mechanisms through which activins regulate Fshb, Gnrhr, and Fst transcription in vitro. The activin signaling molecules SMAD3 and SMAD4 appear to partner with the winged-helix/forkhead transcription factor, forkhead box L2 (FOXL2), to regulate expression of all 3 genes. However, in vivo data paint a different picture. Although conditional deletion of Foxl2 and/or Smad4 in murine gonadotropes produces impairments in FSH synthesis and secretion as well as in pituitary Fst expression, Gnrhr mRNA levels are either unperturbed or increased in these animals. Surprisingly, gonadotrope-specific deletion of Smad3 alone or with Smad2 does not impair FSH production or fertility; however, mice harboring these mutations may express a DNA binding-deficient, but otherwise functional, SMAD3 protein. Collectively, the available data firmly establish roles for FOXL2 and SMAD4 in Fshb and Fst expression in gonadotrope cells, whereas SMAD3's role requires further investigation. Gnrhr expression, in contrast, appears to be FOXL2, SMAD4, and, perhaps, activin independent in vivo.
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Jérôme
J
Fortin
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Luisina
L
Ongaro
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Yining
Y
Li
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Stella
S
Tran
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Pankaj
P
Lamba
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Ying
Y
Wang
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Xiang
X
Zhou
Department of Pharmacology and Therapeutics (J.F., L.O., Y.L., S.T., P.L., Y.W., X.Z., D.J.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; The Campbell Family Cancer Research Institute (J.F.), Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1; Diabetes Center (S.T.), Department of Medicine, University of California-San Francisco, San Francisco, California 94143; and Psychiatry (P.L.), St Mary Mercy Hospital, Livonia, Michigan 48154.
Daniel J
DJ
Bernard
D028341:Activins / Q000378:metabolism*; D000818:Animals; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D052681:Gonadotrophs / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D051785:Smad Proteins; D028341:Activins