Skip to main content

Advertisement

SpringerLink
Log in

GnRH-Mediated DAN Production Regulates the Transcription of the GnRH Receptor in Gonadotrope Cells

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

The primary function of gonadotropin-releasing hormone (GnRH) is the regulation of pituitary gonadotropin hormone gene transcription, biosynthesis and release. These effects are mediated through intracellular mobilization of Ca2+ and activation of PKC isoforms and MAP kinases. We show here that DAN (differential screening-selected gene aberrative in neuroblastoma) which is a secreted bone morphogenic protein (BMP) antagonist belonging to the TGFβ protein superfamily, is controlled by GnRH in murine gonadotrope cells. Acute GnRH stimulation induced a rapid, 27-fold, elevation of DAN mRNA, accompanied by an approximate 3-fold increase in the amount of mature DAN glycoprotein in the cell cytoplasm and in DAN secretion into the culture medium. Incubation of LβT2 cells in DAN-containing medium altered the levels of a number of cellular proteins. Two of these were identified as the steroidogenic acute regulatory protein (StAR) and the actin-related protein 2/3 complex subunits 2 (p34-ARC) which are primarily involved in steroidogenesis and cytoskeleton remodelling, respectively. DAN caused an approximate 2-fold specific elevation in the cytoplasmic levels of both these proteins in LβT2 cells. We further tested the effects of DAN on classical GnRH effects viz. gonadotropin and GnRH receptor gene expression. Co-transfection of LβT2 cells with DAN and gonadotropin subunit promoter luciferase reporter genes had no effect on GnRH stimulation of αGSU and LHβ or on the additive GnRH and activin induction of FSHβ subunit transcription. However, co-transfection of DAN markedly inhibited the synergistic activation of GnRH and activin on GnRH receptor gene expression thus implicating DAN as a novel autocrine/paracrine factor that modulates GnRH function in pituitary gonadotropes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Avsian-Kretchmer, O., & Hsueh, A. J. (2004). Comparative genomic analysis of the eight-membered ring cysteine knot-containing bone morphogenetic protein antagonists. Molecular Endocrinology, 18, 1–12.

    Article  PubMed  CAS  Google Scholar 

  • Bailey, J. S., Rave-Harel, N., McGillivray, S. M., Coss, D., & Mellon, P. L. (2004). Activin regulation of the follicle-stimulating hormone beta-subunit gene involves Smads and the TALE homeodomain proteins Pbx1 and Prep1. Molecular Endocrinology, 18, 1158–1170.

    Article  PubMed  CAS  Google Scholar 

  • Bedecarrats, G. Y., O’Neill, F. H., Norwitz, E. R., Kaiser, U. B., & Teixeira, J. (2003). Regulation of gonadotropin gene expression by Mullerian inhibiting substance. Proceedings of the National Academy of Sciences of the United States of America, 100, 9348–9353.

    Article  PubMed  CAS  Google Scholar 

  • Bjorkhem, I. (2002). Do oxysterols control cholesterol homeostasis? The Journal of Clinical Investigation, 110, 725–730.

    Article  PubMed  CAS  Google Scholar 

  • Brown, P., McNeilly, J. R., Evans, J. G., Crawford, G. M., Walker, M., Christian, H. C., & McNeilly, A. S. (2001). Manipulating the in vivo mRNA expression profile of FSH beta to resemble that of LH beta does not promote a concomitant increase in intracellular storage of follicle-stimulating hormone. Journal of Neuroendocrinology, 13, 50–62.

    Article  PubMed  CAS  Google Scholar 

  • Cameron, V. A., Nishimura, E., Mathews, L. S., Lewis, K. A., Sawchenko, P. E., & Vale, W. W. (1994). Hybridization histochemical localization of activin receptor subtypes in rat brain, pituitary, ovary, and testis. Endocrinology, 134, 799–808.

    Article  PubMed  CAS  Google Scholar 

  • Chang, H., Brown, C. W., & Matzuk, M. M. (2002). Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocrine Reviews, 23, 787–823.

    Article  PubMed  CAS  Google Scholar 

  • Davidson, L., Pawson, A. J., Millar, R. P., & Maudsley, S. (2004). Cytoskeletal reorganization dependence of signaling by the gonadotropin-releasing hormone receptor. The Journal of Biological Chemistry, 279, 1980–1993.

    Article  PubMed  CAS  Google Scholar 

  • Dionne, M. S., Skarnes, W. C., & Harland, R. M. (2001). Mutation and analysis of Dan, the founding member of the Dan family of transforming growth factor beta antagonists. Molecular and Cellular Biology, 21, 636–643.

    Article  PubMed  CAS  Google Scholar 

  • Duenker, N. (2005). Transforming growth factor-beta (TGF-beta) and programmed cell death in the vertebrate retina. International Review of Cytology, 245, 17–43.

    PubMed  CAS  Google Scholar 

  • Duval, D. L., Nelson, S. E., & Clay, C. M. (1997). The tripartite basal enhancer of the gonadotropin-releasing hormone (GnRH) receptor gene promoter regulates cell-specific expression through a novel GnRH receptor activating sequence. Molecular Endocrinology, 11, 1814–1821.

    Article  PubMed  CAS  Google Scholar 

  • Ekshyan, O., & Aw, T. Y. (2004). Apoptosis: A key in neurodegenerative disorders. Current Neurovascular Research, 1, 355–371.

    Article  Google Scholar 

  • Enomoto, H., Ozaki, T., Takahashi, E., Nomura, N., Tabata, S., Takahashi, H., Ohnuma, N., Tanabe, M., Iwai, J., Yoshida, H., et al. (1994). Identification of human DAN gene, mapping to the putative neuroblastoma tumor suppressor locus. Oncogene, 9, 2785–2791.

    PubMed  CAS  Google Scholar 

  • Fitzpatrick, S. L., Sindoni, D. M., Shughrue, P. J., Lane, M. V., Merchenthaler, I. J., & Frail, D. E. (1998). Expression of growth differentiation factor-9 messenger ribonucleic acid in ovarian and non ovarian rodent and human tissues. Endocrinology, 139, 2571–2578.

    Article  PubMed  CAS  Google Scholar 

  • Furukawa, A., Miyatake, A., Ohnishi, T., & Ichikawa, Y. (1998). Steroidogenic acute regulatory protein (StAR) transcripts constitutively expressed in the adult rat central nervous system: Colocalization of StAR, cytochrome P-450SCC (CYP XIA1), and 3beta-hydroxysteroid dehydrogenase in the rat brain. Journal of Neurochemistry, 71, 2231–2238.

    Article  PubMed  CAS  Google Scholar 

  • Granger, A., Ngo-Muller, V., Bleux, C., Guigon, C., Pincas, H., Magre, S., Daegelen, D., Tixier-Vidal, A., Counis, R., & Laverriere, J. N. (2004). The promoter of the rat gonadotropin-releasing hormone receptor gene directs the expression of the human placental alkaline phosphatase reporter gene in gonadotrope cells in the anterior pituitary gland as well as in multiple extrapituitary tissues. Endocrinology, 145, 983–993.

    Article  PubMed  CAS  Google Scholar 

  • Haisenleder, D. J., Dalkin, A. C., Ortolano, G. A., Marshall, J. C., & Shupnik, M. A. (1991). A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: Evidence for differential regulation of transcription by pulse frequency in vivo. Endocrinology, 128, 509–517.

    Article  PubMed  CAS  Google Scholar 

  • Hanaoka, E., Ozaki, T., Nakamura, Y., Moriya, H., Nakagawara, A., & Sakiyama, S. (2000). Overexpression of DAN causes a growth suppression in p53-deficient SAOS-2 cells. Biochemical and Biophysical Research Communications, 278, 20–26.

    Article  PubMed  CAS  Google Scholar 

  • Hsu, D. R., Economides, A. N., Wang, X., Eimon, P. M., & Harland, R. M. (1998). The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Molecular Cell, 1, 673–683.

    Article  PubMed  CAS  Google Scholar 

  • Huang, H. J., Sebastian, J., Strahl, B. D., Wu, J. C., & Miller, W. L. (2001a). Transcriptional regulation of the ovine follicle-stimulating hormone-beta gene by activin and gonadotropin-releasing hormone (GnRH): Involvement of two proximal activator protein-1 sites for GnRH stimulation. Endocrinology, 142, 2267–2274.

    Article  PubMed  CAS  Google Scholar 

  • Huang, H. J., Wu, J. C., Su, P., Zhirnov, O., & Miller, W. L. (2001b). A novel role for bone morphogenetic proteins in the synthesis of follicle-stimulating hormone. Endocrinology, 142, 2275–2283.

    Article  PubMed  CAS  Google Scholar 

  • Hurley, F. M., Costello, D. J., & Sullivan, A. M. (2002). Neuroprotective effects of growth/differentiation factor-5 in a rat model of Parkinson’s disease. Journal of Anatomy, 200, 213.

    Google Scholar 

  • Hurley, F. M., Costello, D. J., & Sullivan, A. M. (2004). Neuroprotective effects of delayed administration of growth/differentiation factor-5 in the partial lesion model of Parkinson’s disease. Experimental Neurology, 185, 281–289.

    Article  PubMed  CAS  Google Scholar 

  • Ito, J., & Yokoyama, S. (2004). Roles of glial cells in cholesterol homeostasis in the brain. In L. Hertz (Ed.), Advances in molecular and cell biology. Non-neuronal cells in the nervous system: Function and dysfunction. Amsterdam: Elsevier Sciences.

  • Jonk, L. J., Itoh, S., Heldin, C. H., ten Dijke, P., & Kruijer, W. (1998). Identification and functional characterization of a SMAD binding element (SBE) in the JunB promoter that acts as a transforming growth factor-beta, activin, and bone morphogenetic protein-inducible enhancer. The Journal of Biological Chemistry, 273, 21145–21152.

    Article  PubMed  CAS  Google Scholar 

  • Kakar, S. S., Winters, S. J., Zacharias, W., Miller, D. M., & Flynn, S. (2003). Identification of distinct gene expression profiles associated with treatment of LbetaT2 cells with gonadotropin-releasing hormone agonist using microarray analysis. Gene, 308, 67–77.

    Article  PubMed  CAS  Google Scholar 

  • Kim, A. S., & Pleasure, S. J. (2003). Expression of the BMP antagonist Dan during murine forebrain development. Brain Research. Developmental Brain Research, 145, 159–162.

    Article  PubMed  CAS  Google Scholar 

  • King, S. R., Manna, P. R., Ishii, T., Syapin, P. J., Ginsberg, S. D., Wilson, K., Walsh, L. P., Parker, K. L., Stocco, D. M., Smith, R. G., et al. (2002). An essential component in steroid synthesis, the steroidogenic acute regulatory protein, is expressed in discrete regions of the brain. The Journal of Neuroscience, 22, 10613–10620.

    PubMed  CAS  Google Scholar 

  • Kraus, S., Naor, Z., & Seger, R. (2001). Intracellular signaling pathways mediated by the gonadotropin-releasing hormone (GnRH) receptor. Archives of Medical Research, 32, 499–509.

    Article  PubMed  CAS  Google Scholar 

  • Larder, R., Chang, L., Clinton, M., & Brown, P. (2004). Gonadotropin-releasing hormone regulates expression of the DNA damage repair gene, Fanconi anemia A, in pituitary gonadotroph cells. Biology of Reproduction, 71, 828–836.

    Article  PubMed  CAS  Google Scholar 

  • Liao, W. X., Moore, R. K., Otsuka, F., & Shimasaki, S. (2003). Effect of intracellular interactions on the processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9. Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep. The Journal of Biological Chemistry, 278, 3713–3719.

    Article  PubMed  CAS  Google Scholar 

  • Lingor, P., Unsicker, K., & Krieglstein, K. (1999). Midbrain dopaminergic neurons are protected from radical induced damage by GDF-5 application. Journal of Neural Transmission, 106, 139–144.

    Article  PubMed  CAS  Google Scholar 

  • Maudsley, S., Pierce, K. L., Zamah, A. M., Miller, W. E., Ahs, S., Daaka, Y., Lefkowitz, R. J., & Luttrell, L. M. (2000). The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. The Journal of Biological Chemistry, 275, 9572–9580.

    Article  PubMed  CAS  Google Scholar 

  • McArdle, C. A., Franklin, J., Green, L., & Hislop, J. N. (2002). Signalling, cycling and desensitization of gonadotrophin-releasing hormone receptors. Journal of Endocrinology, 173, 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Meethal, S. V., Smith, M. A., Bowen, R. L., & Atwood, C. S. (2005). The gonadotropin connection in Alzheimer’s disease. Endocrine, 26, 317–326.

    Article  PubMed  CAS  Google Scholar 

  • Millar, R. P., Lowe, S., Conklin, D., Pawson, A., Maudsley, S., Troskie, B., Ott, T., Millar, M., Lincoln, G., Sellar, R., Faurholm, B., et al. (2001). A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proceedings of the National Academy of Sciences of the United States of America, 98, 9636–9641.

    Article  PubMed  CAS  Google Scholar 

  • Millar, R. P., Lu, Z.-L., Pawson, A. J., Flanagan, C. A., Morgan, K., & Maudsley, S. (2004). Gonadotropin-releasing hormone receptors. Endocrine Reviews, 25, 235–275.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura, Y., Ozaki, T., Nakagawara, A., & Sakiyama, S. (1997). A product of DAN, a novel candidate tumour suppressor gene, is secreted into culture medium and suppresses DNA synthesis. European Journal of Cancer, 33, 1986–1990.

    Article  PubMed  CAS  Google Scholar 

  • Nakamura, Y., Ozaki, T., Ichimiya, S., Nakagawara, A., & Sakiyama, S. (1998). Ectopic expression of DAN enhances the retinoic acid-induced neuronal differentiation in human neuroblastoma cell lines. Biochemical and Biophysical Research Communications, 243, 722–726.

    Article  PubMed  CAS  Google Scholar 

  • Navratil, A. M., Bliss, S. P., Berghorn, K. A., Haughian, J. M., Farmerie, T. A., Graham, J. K., Clay, C. M., & Roberson, M. S. (2003). Constitutive localization of the gonadotropin-releasing hormone (GnRH) receptor to low density membrane microdomains is necessary for GnRH signaling to ERK. The Journal of Biological Chemistry, 278, 31593–31602.

    Article  PubMed  CAS  Google Scholar 

  • Nelson, J. F., Gosden, R. G., & Felicio, L. S. (1985). Effect of dietary restriction on estrous cyclicity and follicular reserves in aging C57BL/6J mice. Biology of Reproduction, 32, 515–522.

    Article  PubMed  CAS  Google Scholar 

  • Norwitz, E. R., Jeong, K. H., & Chin, W. W. (1999a). Molecular mechanisms of gonadotropin-releasing hormone receptor gene regulation. Journal of the Society for Gynecologic Investigation, 6, 169–178.

    Article  PubMed  CAS  Google Scholar 

  • Norwitz, E. R., Cardona, G. R., Jeong, K. H., & Chin, W. W. (1999b). Identification and characterization of the gonadotropin-releasing hormone response elements in the mouse gonadotropin-releasing hormone receptor gene. The Journal of Biological Chemistry, 274, 867–880.

    Article  PubMed  CAS  Google Scholar 

  • Norwitz, E. R., Xu, S., Jeong, K. H., Bedecarrats, G. Y., Winebrenner, L. D., Chin, W. W., & Kaiser, U. B. (2002a). Activin A augments GnRH-mediated transcriptional activation of the mouse GnRH receptor gene. Endocrinology, 143, 985–997.

    Article  PubMed  CAS  Google Scholar 

  • Norwitz, E. R., Xu, S., Xu, J., Spiryda, L. B., Park, J. S., Jeong, K. H., McGee, E. A., & Kaiser, U. B. (2002b). Direct binding of AP-1 (Fos/Jun) proteins to a SMAD binding element facilitates both gonadotropin-releasing hormone (GnRH)- and activin-mediated transcriptional activation of the mouse GnRH receptor gene. The Journal of Biological Chemistry, 277, 37469–37478.

    Article  PubMed  CAS  Google Scholar 

  • Ohtori, S., Yamamoto, T., Ino, H., Hanaoka, E., Shinbo, J., Ozaki, T., Takada, N., Nakamura, Y., Chiba, T., Nakagawara, A., et al. (2002). Differential screening-selected gene aberrative in neuroblastoma protein modulates inflammatory pain in the spinal dorsal horn. Neuroscience, 110, 579–586.

    Article  PubMed  CAS  Google Scholar 

  • Ohtori, S., Isogai, E., Hasue, F., Ozaki, T., Nakamura, Y., Nakagawara, A., Koseki, H., Yuasa, S., Hanaoka, E., Shinbo, J., et al. (2004). Reduced inflammatory pain in mice deficient in the differential screening-selected gene aberrative in neuroblastoma. Molecular and Cellular Neurosciences, 25, 504–514.

    Article  PubMed  CAS  Google Scholar 

  • O’Keefe, G. W., Hanke, M., Pohl, J., & Sullivan A. M. (2004). Expression of growth/differentiation factor 5 in the developing and adult rat brain. Brain Research. Developmental Brain Research, 151, 199–202.

    Article  CAS  Google Scholar 

  • Otsuka, F., & Shimasaki, S. (2002). A novel function of bone morphogenetic protein-15 in the pituitary: Selective synthesis and secretion of FSH by gonadotropes. Endocrinology, 143, 4938–4941.

    Article  PubMed  CAS  Google Scholar 

  • Ott, T. R., Troskie, B. E., Roeske, R. W., Illing, N., Flanagan, C. A., & Millar, R. P. (2002). Two mutations in extracellular loop 2 of the human GnRH receptor convert an antagonist to an agonist. Molecular Endocrinology, 16, 1079–1088.

    Article  PubMed  CAS  Google Scholar 

  • Ozaki, T., & Sakiyama, S. (1993). Molecular cloning and characterization of a cDNA showing negative regulation in v-src-transformed 3Y1 rat fibroblasts. Proceedings of the National Academy of Sciences of the United States of America, 90, 2593–2597.

    Article  PubMed  CAS  Google Scholar 

  • Ozaki, T., & Sakiyama, S. (1994). Tumor-suppressive activity of N03 gene product in v-src-transformed rat 3Y1 fibroblasts. Cancer Research, 54, 646–648.

    PubMed  CAS  Google Scholar 

  • Papavasiliou, S. S., Zmeili, S., Khoury, S., Landefeld, T. D., Chin, W. W., & Marshall, J. C. (1986). Gonadotropin-releasing hormone differentially regulates expression of the genes for luteinizing hormone alpha and beta subunits in male rats. Proceedings of the National Academy of Sciences of the United States of America, 83, 4026–4029.

    Article  PubMed  CAS  Google Scholar 

  • Pawson, A. J., Maudsley, S. R., Lopes, J., Katz, A. A., Sun, Y. M., Davidson, J. S., & Millar, R. P. (2003). Multiple determinants for rapid agonist-induced internalization of a nonmammalian gonadotropin-releasing hormone receptor: A putative palmitoylation site and threonine doublet within the carboxyl-terminal tail are critical. Endocrinology, 144, 3860–2871.

    Article  PubMed  CAS  Google Scholar 

  • Pearce, J. J., Penny, G., & Rossant, J. (1999). A mouse cerberus/Dan-related gene family. Developmental Biology, 209, 98–110.

    Article  PubMed  CAS  Google Scholar 

  • Pernasetti, F., Vasilyev, V. V., Rosenberg, S. B., Bailey, J. S., Huang, H. J., Miller, W. L., & Mellon, P. L. (2001). Cell-specific transcriptional regulation of follicle-stimulating hormone-beta by activin and gonadotropin-releasing hormone in the LbetaT2 pituitary gonadotrope cell model. Endocrinology, 142, 2284–2295.

    Article  PubMed  CAS  Google Scholar 

  • Pincas, H., Amoyel, K., Counis, R., & Laverriere, J. N. (2001). Proximal cis-acting elements, including steroidogenic factor 1, mediate the efficiency of a distal enhancer in the promoter of the rat gonadotropin-releasing hormone receptor gene. Molecular Endocrinology, 15, 319–337.

    Article  PubMed  CAS  Google Scholar 

  • Plassart-Schiess, E., & Baulieu, E. E. (2001). Neurosteroids: Recent findings. Brain Research. Brain Research Reviews, 37, 133–140.

    Article  PubMed  CAS  Google Scholar 

  • Quirk, J., & Brown, P. (2002). Hesx1 homeodomain protein represses transcription as a monomer and antagonises transactivation of specific sites as a homodimer. Journal of Molecular Endocrinology, 28, 193–205.

    Article  PubMed  CAS  Google Scholar 

  • Roth, B. L. (2000). Neuronal signal transduction pathways: Wasteland or the promised land? Science’s STKE, 15, 1–3.

    Google Scholar 

  • Ruf, F., Fink, M. Y., & Sealfon, S. C. (2003). Structure of the GnRH receptor-stimulated signaling network: Insights from genomics. Frontiers in Neuroendocrinology, 24, 181–199.

    Article  PubMed  CAS  Google Scholar 

  • Sakiyama, S., Ozaki, T., & Enomoto, H. (1994). Molecular cloning and characterization of a cDNA showing tumor-suppressive activity in V-SRC-transformed 3Y1 rat fibroblasts. Advances in Enzyme Regulation, 34, 247–255.

    Article  PubMed  CAS  Google Scholar 

  • Schroeder, F., Gallegos, A. M., Atshaves, B. P., Storey, S. M., McIntosh, A. L., Petrescu, A. D., Huang, H., Starodub, O., Chao, H., Yang, H., Frolov, A., & Kier, A. B. (2001). Recent advances in membrane microdomains: Rafts, caveolae, and intracellular cholesterol trafficking. Experimental Biology and Medicine, 226, 873–890.

    PubMed  CAS  Google Scholar 

  • Schroepfer, G. J., Jr. (2000). Oxysterols: Modulators of cholesterol metabolism and other processes. Physiological Reviews, 80, 361–554.

    PubMed  CAS  Google Scholar 

  • Session, D. R., Pearlstone, M. M., Jewelewicz, R., & Kelly, A. C. (1994). Estrogens and Parkinson’s disease. Medical Hypotheses, 42, 280–282.

    Article  PubMed  CAS  Google Scholar 

  • Sharpe, R. M., Martin, B., Morris, K., Greig, I., McKinnell, C., McNeilly, A. S., & Walker, M. (2002). Infant feeding with soy formula milk: Effects on the testis and on blood testosterone levels in marmoset monkeys during the period of neonatal testicular activity. Human Reproduction, 17, 1692–1703.

    Article  PubMed  CAS  Google Scholar 

  • Shi, Y., & Massague, J. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 113, 685–700.

    Article  PubMed  CAS  Google Scholar 

  • Shimasaki, S., Moore, R. K., Otsuka, F., & Erickson, G. F. (2004). The bone morphogenetic protein system in mammalian reproduction. Endocrine Reviews, 25, 72–101.

    Article  PubMed  CAS  Google Scholar 

  • Sierra, A., Lavaque, E., Perez-Martin, M., Azcoitia, I., Hales, D. B., & Garcia-Segura, L. M. (2003). Steroidogenic acute regulatory protein in the rat brain: Cellular distribution, developmental regulation and overexpression after injury. The European Journal of Neuroscience, 18, 1458–1467.

    Article  PubMed  Google Scholar 

  • Sierra, A. (2004). Neurosteroids: The StAR protein in the brain. Journal of Neuroendocrinology, 16, 787–793.

    Article  PubMed  CAS  Google Scholar 

  • Stanley, E., Biben, C., Kotecha, S., Fabri, L., Tajbakhsh, S., Wang, C. C., Hatzistavrou, T., Roberts, B., Drinkwater, C., et al. (1998). DAN is a secreted glycoprotein related to Xenopus cerberus. Mechanisms of Development, 77, 173–184.

    Article  PubMed  CAS  Google Scholar 

  • Stocco, D. M. (1999). Steroidogenic acute regulatory (StAR) protein: What’s new? Bioessays, 21, 768–775.

    Article  PubMed  CAS  Google Scholar 

  • Storm, E. E., Huynh, T. V., Copeland, N. G., Jenkins, N. A., Kingsley, D. M., & Lee, S. J. (1994). Limb alterations in brachypodism mice due to mutations in a new member of the TGF-beta superfamily. Nature, 368, 639–643.

    Article  PubMed  CAS  Google Scholar 

  • Sudo, S., Avsian-Kretchmer, O., Wang, L. S., & Hsueh, A. J. (2004). Protein related to DAN and cerberus is a bone morphogenetic protein antagonist that participates in ovarian paracrine regulation. The Journal of Biological Chemistry, 279, 23134–23141.

    Article  PubMed  CAS  Google Scholar 

  • Sugawara, T., Holt, J. A., Driscoll, D., Strauss, J. F., III, Lin, D., Miller, W. L., Patterson, D., Clancy, K. P., Hart, I. M., Clark, B. J., et al. (1995). Human steroidogenic acute regulatory protein: Functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13. Proceedings of the National Academy of Sciences of the United States of America, 92, 4778–4782.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan, A. M., & O’Keefe, G. W. (2005). The role of growth/differentiation factor 5 (GDF5) in the induction and survival of midbrain dopaminergic neurones: Relevance to Parkinson’s disease treatment. Journal of Anatomy, 207, 219–226.

    Article  PubMed  CAS  Google Scholar 

  • Sullivan, A. M., Pohl, J., & Blunt, S. B. (1998). Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson’s disease. European Journal of Neuroscience, 10, 3681–3688.

    Article  PubMed  CAS  Google Scholar 

  • Tamas, A., Lubics, A., Szalontay, L., Lengvari, I., & Reglodi, D. (2005). Age and gender differences in behavioural and morphological outcome after 6-hydroxydopamine-induced lesion of the substantia nigra in rats. Behavioural Brain Research, 158, 221–229.

    Article  PubMed  CAS  Google Scholar 

  • Turgeon, J. L., Kimura, Y., Waring, D. W., & Mellon, P. L. (1996). Steroid and pulsatile gonadotropin-releasing hormone (GnRH) regulation of luteinizing hormone and GnRH receptor in a novel gonadotrope cell line. Molecular Endocrinology, 10, 439–450.

    Article  PubMed  CAS  Google Scholar 

  • Welch, M. D., DePace, A. H., Verma, S., Iwamatsu, A., & Mitchison, T. J. (1997). The human Arp2/3 complex is composed of evolutionarily conserved subunits and is localized to cellular regions of dynamic actin filament assembly. The Journal of Cell Biology, 138, 375–384.

    Article  PubMed  CAS  Google Scholar 

  • White, P. S., Maris, J. M., Beltinger, C., Sulman, E., Marshall, H. N., Fujimori, M., Kaufman, B. A., Biegel, J. A., Allen, C., Hilliard, C., et al. (1995). A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2–36.3. Proceedings of the National Academy of Sciences of the United States of America, 92, 5520–5524.

    Article  PubMed  CAS  Google Scholar 

  • Windle, J. J., Weiner, R. I., & Mellon, P. L. (1990). Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Molecular Endocrinology, 4, 597–603.

    Article  PubMed  CAS  Google Scholar 

  • Wurmbach, E., Yuen, T., Ebersole, B. J., & Sealfon, S. C. (2001). Gonadotropin-releasing hormone receptor-coupled gene network organization. The Journal of Biological Chemistry, 276, 47195–47201.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, X., Yang, Z., Qian, M., & Zhu, X. (2001). Interactions among subunits of human Arp2/3 complex: p20-Arc as the hub. Biochemical and Biophysical Research Communications, 280, 513–517.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Bronwen Martin

    Present address: NIH, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA

  2. Rakel López de Maturana

    Present address: Department of Pharmacology, University of the Basque Country, Paseo de la Universidad 7, Vitoria-Gasteiz, 01006, Spain

  3. Lindsay Davidson

    Present address: Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

Authors and Affiliations

  1. MRC Human Reproductive Sciences Unit, Centre for Human Reproductive Biology, Edinburgh, EH16 4SB, UK

    Rakel López de Maturana, Bronwen Martin, Robert P. Millar, Pamela Brown, Lindsay Davidson, Adam J. Pawson, Zvi Naor & Stuart Maudsley

  2. Ardana Bioscience, 38 Melville Street, Edinburgh, EH3 7HA, UK

    Rakel López de Maturana

  3. Division of Reproductive & Developmental Science, Centre for Reproductive Biology, The Chancellor’s Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK

    Moira R. Nicol & J. Ian Mason

  4. Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK

    Perdita Barran

  5. Department of Biochemistry, Tel Aviv University, Tel Aviv, 69975, Israel

    Zvi Naor

  6. NIH, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA

    Stuart Maudsley

Authors
  1. Rakel López de Maturana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bronwen Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert P. Millar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pamela Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lindsay Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adam J. Pawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Moira R. Nicol
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Ian Mason
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Perdita Barran
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zvi Naor
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stuart Maudsley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stuart Maudsley.

Additional information

Rakel López de Maturana and Bronwen Martin contributed equally to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

López de Maturana, R., Martin, B., Millar, R.P. et al. GnRH-Mediated DAN Production Regulates the Transcription of the GnRH Receptor in Gonadotrope Cells. Neuromol Med 9, 230–248 (2007). https://doi.org/10.1007/s12017-007-8004-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-007-8004-z

Keywords

Search

Navigation