Molecular Mechanisms of Gonadotrope Differentiation

Summary

Principal Investigator: PAMELA MELLON
Abstract: DESCRIPTION: The anterior pituitary synthesizes hormones that control reproduction, homeostasis, growth, stress response, and lactation. Since each of these physiological responses must be regulated independently, individual pituitary endocrine cell types are specialized to produce distinct hormones. During development, each cell lineage arises in a unique spatial and temporal pattern. The gonadotrope, which regulates reproductive function through the synthesis of the gonadotropins Luteinizing Hormone (LH) and Follicle- Stimulating Hormone (FSH), arises last in this process, as defined by the appearance of the beta subunits of its hallmark proteins. However, its emergence can be traced throughout pituitary development by the sequential appearance of earlier markers of the lineage, first the alpha subunit shared by LH, FSH and Thyroid-Stimulating Hormone, followed by the orphan nuclear receptor Steroidogenic Factor 1, then Gonadotropin-Releasing Hormone Receptor, and finally the LH beta and FSH beta subunits. Using targeted tumorigenesis in transgenic mice, we have developed immortalized cell lines that represent sequential developmental stages of the gonadotrope lineage and the closely related thyrotrope. Utilizing these novel cell models coupled with genetic manipulation in vivo, we propose to elucidate the program of regulators involved in the progression of differentiation to the mature gonadotrope. In the first three aims, we will focus on three select classes of regulatory factors, GATA-binding proteins, basic helix-loop-helix proteins, and LIM-homeodomain proteins. Members of each family are known to directly regulate gonadotropin subunit genes and to be involved in specification of pituitary lineages;however, the balance, interplay, and timing of their actions and those of their co-factors remain to be delineated. These DNA- binding proteins and their associated co-regulators are themselves regulated during lineage progression. Our hypothesis is that programs of closely related factors and their associated co-regulators sequentially occupy control elements in gonadotrope target genes to determine lineage progression and maturation. In the fourth aim, we will take an unbiased approach to defining the mature gonadotrope phenotype at the molecular level, utilizing innovative bioinformatic and molecular methods to identify key components of the gonadotrope differentiation program.
Funding Period: ----------------1992 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Activin modulates the transcriptional response of LbetaT2 cells to gonadotropin-releasing hormone and alters cellular proliferation
    Hao Zhang
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0673, USA
    Mol Endocrinol 20:2909-30. 2006
  2. pmc Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes
    Emily A Witham
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093 0674, USA
    Mol Endocrinol 27:1283-94. 2013
  3. pmc Neurokinin B causes acute GnRH secretion and repression of GnRH transcription in GT1-7 GnRH neurons
    Christine A Glidewell-Kenney
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093 0674, USA
    Mol Endocrinol 27:437-54. 2013
  4. pmc Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6
    Daniel D Clark
    Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA, USA
    J Biol Rhythms 28:15-25. 2013
  5. pmc Msx1 homeodomain protein represses the αGSU and GnRH receptor genes during gonadotrope development
    Huimin Xie
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA 92093 0674, USA
    Mol Endocrinol 27:422-36. 2013
  6. pmc Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1
    Melissa J Brayman
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093 0674, USA
    Mol Cell Endocrinol 363:92-9. 2012
  7. pmc Stress levels of glucocorticoids inhibit LHβ-subunit gene expression in gonadotrope cells
    Kellie M Breen
    Department of Reproductive Medicine Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 26:1716-31. 2012
  8. pmc Prenatal exposure to low levels of androgen accelerates female puberty onset and reproductive senescence in mice
    Emily A Witham
    Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, USA
    Endocrinology 153:4522-32. 2012
  9. pmc NeuroD1 and Mash1 temporally regulate GnRH receptor gene expression in immortalized mouse gonadotrope cells
    Brian D Cherrington
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    Mol Cell Endocrinol 295:106-14. 2008
  10. pmc Androgens, progestins, and glucocorticoids induce follicle-stimulating hormone beta-subunit gene expression at the level of the gonadotrope
    Varykina G Thackray
    Department of Reproductive Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 20:2062-79. 2006

Scientific Experts

  • Daiane Beneduzzi
  • Pamela L Mellon
  • Varykina G Thackray
  • Djurdjica Coss
  • Jason D Meadows
  • Emily A Witham
  • Melissa J Brayman
  • Anita K Iyer
  • Nicholas J G Webster
  • Kellie M Breen
  • Rachel Larder
  • Nichol L G Miller
  • Daniel D Clark
  • Shweta Sharma
  • Yasmin Ghochani
  • Jerrold M Olefsky
  • Heather A Ely
  • Brian D Cherrington
  • Min Lu
  • Shauna M McGillivray
  • Mark A Lawson
  • Hao Zhang
  • Huimin Xie
  • Christine A Glidewell-Kenney
  • Alexander S Kauffman
  • Shadi Shojaei
  • Patricia A Pepa
  • Debin Lan
  • Patrick S Corpuz
  • José E Avelino-Cruz
  • Ravid Sasson
  • Janice S Bailey
  • Nelly Pitteloud
  • Rie Tsutsumi
  • Michael R Gorman
  • Megumi Hatori
  • Anna M H Grove
  • Paul P Shao
  • Satchidananda Panda
  • Hanne M Hoffmann
  • Jasjit K Saini
  • Sara E Berdy
  • Rachel A Mak-McCully
  • Tracy Hsu
  • Prem M Sharma
  • Devendra S Mistry
  • R Jeffery Chang
  • Kathleen Yip
  • Brian H Tran
  • Lacey L Lindaman
  • Amira Flores
  • Aisha K Memon
  • Eduardo Monjaraz
  • Jennifer L Hunnicutt
  • Rachel Wevrick
  • Ricardo Felix
  • Jorge Cebada
  • Sang H Luu
  • Qingbo Tang
  • Alejandro L Diaz
  • Indrani Talukdar
  • Sharon J Santos
  • Elka E Jacobson-Dickman
  • Lindsay W Cole
  • Lacey Plummer
  • Karen K J Yaphockun
  • Qun Yong Zhou
  • Jia Da Li
  • William F Crowley
  • Duarte Pignatelli
  • Chengkang Zhang
  • Cameron M Hand
  • Brian K Butler
  • Taneli Raivio
  • Bo Lin

Detail Information

Publications34

  1. pmc Activin modulates the transcriptional response of LbetaT2 cells to gonadotropin-releasing hormone and alters cellular proliferation
    Hao Zhang
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0673, USA
    Mol Endocrinol 20:2909-30. 2006
    ....
  2. pmc Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes
    Emily A Witham
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093 0674, USA
    Mol Endocrinol 27:1283-94. 2013
    ....
  3. pmc Neurokinin B causes acute GnRH secretion and repression of GnRH transcription in GT1-7 GnRH neurons
    Christine A Glidewell-Kenney
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093 0674, USA
    Mol Endocrinol 27:437-54. 2013
    ..Furthermore, whether the response is inhibitory or stimulatory toward GnRH secretion could depend on the history or length of exposure to NKB because of a repressive effect on GnRH transcription...
  4. pmc Aberrant development of the suprachiasmatic nucleus and circadian rhythms in mice lacking the homeodomain protein Six6
    Daniel D Clark
    Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA, USA
    J Biol Rhythms 28:15-25. 2013
    ..Therefore, Six6 is required for the normal development of the SCN, and the Six6-null mouse can mount independent, although irregular, circadian rhythms despite the apparent absence of a histochemically defined SCN...
  5. pmc Msx1 homeodomain protein represses the αGSU and GnRH receptor genes during gonadotrope development
    Huimin Xie
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, CA 92093 0674, USA
    Mol Endocrinol 27:422-36. 2013
    ....
  6. pmc Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1
    Melissa J Brayman
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093 0674, USA
    Mol Cell Endocrinol 363:92-9. 2012
    ..We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at -1792/-1791...
  7. pmc Stress levels of glucocorticoids inhibit LHβ-subunit gene expression in gonadotrope cells
    Kellie M Breen
    Department of Reproductive Medicine Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 26:1716-31. 2012
    ....
  8. pmc Prenatal exposure to low levels of androgen accelerates female puberty onset and reproductive senescence in mice
    Emily A Witham
    Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093, USA
    Endocrinology 153:4522-32. 2012
    ..Thus, prenatal, but not prepubertal, exposure to low levels of androgens disrupts normal reproductive function throughout life from puberty to reproductive senescence...
  9. pmc NeuroD1 and Mash1 temporally regulate GnRH receptor gene expression in immortalized mouse gonadotrope cells
    Brian D Cherrington
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    Mol Cell Endocrinol 295:106-14. 2008
    ....
  10. pmc Androgens, progestins, and glucocorticoids induce follicle-stimulating hormone beta-subunit gene expression at the level of the gonadotrope
    Varykina G Thackray
    Department of Reproductive Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 20:2062-79. 2006
    ..Our data indicate that androgens, glucocorticoids, and progestins act via their receptors to directly activate FSHbeta gene expression in the pituitary gonadotrope...
  11. pmc Activin and glucocorticoids synergistically activate follicle-stimulating hormone beta-subunit gene expression in the immortalized LbetaT2 gonadotrope cell line
    Shauna M McGillivray
    Department of Reproductive Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Endocrinology 148:762-73. 2007
    ..Our studies provide the first evidence of a synergistic interaction between activin and glucocorticoids within the gonadotrope cell and demonstrate that this synergy can occur directly at the level of the mouse FSHbeta promoter...
  12. pmc Pulse sensitivity of the luteinizing hormone beta promoter is determined by a negative feedback loop Involving early growth response-1 and Ngfi-A binding protein 1 and 2
    Mark A Lawson
    Department of Reproductive Medicine 0674, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 21:1175-91. 2007
    ..This pattern of expression suggests a model of pulse frequency detection that acts by suppressing activation by Egr family members at low frequency and allowing activation at sustained high-frequency pulses...
  13. pmc p38 mitogen-activated protein kinase is critical for synergistic induction of the FSH(beta) gene by gonadotropin-releasing hormone and activin through augmentation of c-Fos induction and Smad phosphorylation
    Djurdjica Coss
    Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 21:3071-86. 2007
    ..Thus, p38 is the pivotal signaling molecule that integrates GnRH and activin interaction on the FSHbeta promoter through higher induction of c-Fos and elevated Smad phosphorylation...
  14. pmc Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism
    Nelly Pitteloud
    Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114, USA
    Proc Natl Acad Sci U S A 104:17447-52. 2007
    ..Homozygous loss-of-function PROK2 mutations cause both KS and nIHH...
  15. pmc Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LbetaT2 gonadotropes
    Min Lu
    Department of Medicine, University of California, San Diego, California 92093, USA
    Mol Endocrinol 22:760-71. 2008
    ..In conclusion, our results suggest that adiponectin decreases LH secretion in pituitary gonadotropes in an AMPK-dependent manner...
  16. pmc Synergistic induction of follicle-stimulating hormone beta-subunit gene expression by gonadal steroid hormone receptors and Smad proteins
    Varykina G Thackray
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    Endocrinology 149:1091-102. 2008
    ....
  17. pmc Glucocorticoids induce human glycoprotein hormone alpha-subunit gene expression in the gonadotrope
    Ravid Sasson
    Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0674, USA
    Endocrinology 149:3643-55. 2008
    ....
  18. pmc Dynamic chromatin modifications control GnRH gene expression during neuronal differentiation and protein kinase C signal transduction
    Anita K Iyer
    Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 25:460-73. 2011
    ..Chromatin modifications therefore participate in the dynamic regulation and specification of GnRH expression to differentiated hypothalamic neurons...
  19. pmc FOXL2 is involved in the synergy between activin and progestins on the follicle-stimulating hormone β-subunit promoter
    Yasmin Ghochani
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California 92093, USA
    Endocrinology 153:2023-33. 2012
    ..Thus, it is likely that protein-protein interactions among FOXL2, SMAD, and PR recruited to the Fshb promoter play a key role in facilitating Fshb transcription before the secondary FSH surge in rodents...
  20. pmc Androgen receptor repression of GnRH gene transcription
    Melissa J Brayman
    Department of Reproductive Medicine and The Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093 0674, USA
    Mol Endocrinol 26:2-13. 2012
    ....
  21. pmc Trans-resveratrol inhibits phosphorylation of Smad2/3 and represses FSHβ gene expression by a SirT1-independent pathway in LβT2 gonadotrope cells
    Debin Lan
    Department of Medicine, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA
    Reprod Toxicol 32:85-92. 2011
    ..Taken together, our results suggest that resveratrol down-regulates Smad2/3 phosphorylation and suppresses FSHβ expression via a SirT1-independent pathway...
  22. pmc Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism
    Daiane Beneduzzi
    Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Avenida Doutor Eneas de Carvalho Aguiar 155, 2 andar, Bloco 6, CEP 05403 900 São Paulo, Sao Paulo, Brazil
    Eur J Endocrinol 165:145-50. 2011
    ..In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome...
  23. pmc GnRH induces the c-Fos gene via phosphorylation of SRF by the calcium/calmodulin kinase II pathway
    Heather A Ely
    Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 25:669-80. 2011
    ..Thus, GnRH uses a combination of growth factor signaling and the CamKII pathway to induce c-Fos to regulate FSHβ gene expression in gonadotrope cells...
  24. pmc Hypothalamic dysregulation and infertility in mice lacking the homeodomain protein Six6
    Rachel Larder
    Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093 0674, USA
    J Neurosci 31:426-38. 2011
    ..Together, these data indicate that Six6 plays an important role in the regulation of GnRH expression and hypothalamic control of fertility...
  25. pmc PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice
    Shweta Sharma
    Medical Research Service, VA San Diego Healthcare System, San Diego, California, USA
    Biol Reprod 84:466-75. 2011
    ..Taken together, our data support a direct role for PPARG in modulating pituitary function in vitro and in vivo...
  26. pmc Enhancers of GnRH transcription embedded in an upstream gene use homeodomain proteins to specify hypothalamic expression
    Anita K Iyer
    Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093 0674, USA
    Mol Endocrinol 24:1949-64. 2010
    ..Thus, GnRH-E2 and GnRH-E3 are novel regulatory elements that, together with GnRH-E1 and GnRH-P, confer the specificity of GnRH expression to differentiated and mature GnRH neurons...
  27. pmc A FoxL in the Smad house: activin regulation of FSH
    Djurdjica Coss
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA, 92093 0674, USA
    Trends Endocrinol Metab 21:562-8. 2010
    ....
  28. pmc Runt-related transcription factors impair activin induction of the follicle-stimulating hormone {beta}-subunit gene
    Kellie M Breen
    Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Endocrinology 151:2669-80. 2010
    ..In summary, the present study provides evidence for Runx2-mediated repression of activin-induced FSHbeta gene expression and reveals the context dependence of Runx2 action in hormonal regulation of the gonadotropin genes...
  29. pmc FoxL2 Is required for activin induction of the mouse and human follicle-stimulating hormone beta-subunit genes
    Patrick S Corpuz
    Department of Reproductive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 0674, USA
    Mol Endocrinol 24:1037-51. 2010
    ..Thus, FoxL2 plays a key role in activin induction of the FSHbeta gene, by binding to sites conserved across multiple species...
  30. pmc Hormones in synergy: regulation of the pituitary gonadotropin genes
    Varykina G Thackray
    Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92093 0674, USA
    Mol Cell Endocrinol 314:192-203. 2010
    ..We also discuss how recent technological advances will help identify additional factors involved in the differential hormonal regulation of LH and FSH...
  31. pmc Otx2 induction of the gonadotropin-releasing hormone promoter is modulated by direct interactions with Grg co-repressors
    Rachel Larder
    Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093 0674, USA
    J Biol Chem 284:16966-78. 2009
    ..Taken together, these data show that Otx2 is important for GnRH expression and that direct interaction between Otx2 and Grg co-repressors regulates GnRH gene expression in hypothalamic neurons...
  32. pmc Progesterone Inhibits basal and gonadotropin-releasing hormone induction of luteinizing hormone beta-subunit gene expression
    Varykina G Thackray
    Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
    Endocrinology 150:2395-403. 2009
    ..Altogether, our data indicate that progesterone feedback at the level of the pituitary gonadotrope is likely to play a key role in differential production of the gonadotropin genes...
  33. pmc Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development
    Nichol L G Miller
    Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0674, USA
    Hum Mol Genet 18:248-60. 2009
    ..Together, these results indicate that lack of necdin during development likely contributes to the hypogonadotrophic hypogonadal phenotype in individuals with PWS...
  34. pmc Leptin increases L-type Ca2+ channel expression and GnRH-stimulated LH release in LbetaT2 gonadotropes
    José E Avelino-Cruz
    Laboratory of Neuroendocrinology, Institute of Physiology, Autonomous University of Puebla BUAP, Puebla, Mexico
    Mol Cell Endocrinol 298:57-65. 2009
    ..These observations suggest that leptin might affect LH release by acting directly on the gonadotropes, favoring hormone production by enhancing responsiveness to GnRH as a result of increased Ca(2+) channel expression...