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Regulation of gonadotropin-releasing hormone (GnRH) gene expression in hypothalamic neuronal cells

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Summary

1. Gonadotropin-releasing hormone (GnRH) is the hypothalamic releasing factor that controls pituitary gonadotropin subunit gene expression and indirectly gametogenesis and steroidogenesis from the gonad, which results in reproductive competence.

2. GnRH is synthesized in only about 1000 neurons in the hypothalamus and released in an episodic fashion down the median eminence to regulate gonadotropin biosynthesis.

3. Although much is known about the secretory dynamics of GnRH release, little is known about the pretranslational control of GnRH biosynthesis due to lack of appropriate model systems. The recent availability of immortalized neuronal cell lines that produce GnRH allows investigators for the first time to begin to dissect the factors that directly regulate GnRH gene expression.

4. This article reviews the current state of knowledge concerning the mechanisms that direct tissue-specific and peptide hormone control of GnRH biosynthesis.

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References

  • Adelman, J. P., Mason, A. J., Hayflick, J. S., and Seeburg, P. H. (1986). Isolation of the gene and hypothalamic cDNA for the common precursor of gonadotropin-releasing hormone and prolactin release-inhibiting factor in human and rat.Proc. Natl. Acad. Sci. USA 83:179–183.

    PubMed  Google Scholar 

  • Adelman, J. P., Bond, C. T., Douglass, J., and Herbert, E. (1987). Two mammalian genes transcribed from opposite strands of the same DNA locus.Science 235:1514–1517.

    PubMed  Google Scholar 

  • Belsham, D. D., Lawson, M. A., Whyte, D. B., and Mellon, P. L. (1994). Hypothalamic regulation of the GnRH gene by a neuron-specific enhancer. Endocrine Society, Abstract No. 1277.

  • Bond, C. T., Hayflick, J. S., Seeburg, P. H., and Adelman, J. P. (1989). The rat gonadotropin-releasing hormone: SH locus: Structure and hypothalamic expression.Mol. Endocrinol. 3:1257–1262.

    PubMed  Google Scholar 

  • Bruder, J. M., and Wierman, M. E. (1993). Protein kinase C (PKC) inhibition of rat GnRH promoter activity is associates with an increase in c-Fos and c-Jun mRNA and mimicked by overexpression of c-Fos and c-Jun. Endocrine Society, Abstract No. 1985.

  • Bruder, J. M., and Wierman, M. E. (1994). Evidence for transcriptional inhibition of GnRH gene expression by phorbol ester at a proximal promoter region.Mol. Cell. Endrocrinol. 99:177–182.

    Google Scholar 

  • Bruder, J. M., Krebs, W. D., Nett, T. M., and Wierman, M. E. (1992). Phorbol ester activation of the protein kinase C pathway inhibits gonadotropin-releasing hormone gene expression.Endocrinology 131:2552–2558.

    PubMed  Google Scholar 

  • Chandran, U. R., Attardi, B., Friedman, R., Dong, K.-W., Roberts, J. L., and DeFranco, D. B. (1994). Glucocorticoid receptor-mediated repression of gonadotropin-releasing hormone promoter activity in GT1 hypothalamic cell lines.Endrocrinology 134:1467–1474.

    Google Scholar 

  • Favit, A., Wetsel, W. C., and Negro-Vilar, A. (1993). Differential expression ofγ-aminobutyric acid receptors in immortalized luteinizing hormone-releasing hormone neurons.Endocrinology 133:1983–1989.

    PubMed  Google Scholar 

  • Hales, T. G., Kim, H., Longoni, B., Olsen, R. W., and Tobin, A. J. (1992). Immortalized hypothalamic GT1-7 neurons express functionalγ-aminobutyric acid type A receptors.Mol. Pharmacol. 42:197–202.

    PubMed  Google Scholar 

  • Hayflick, J. S., Adelman, J. P., and Seeburg, P. H. (1989). The complete nucleotide sequence of the human gonadotropin-releasing hormone gene.Nucleic Acids Res. 17:6403–6404.

    PubMed  Google Scholar 

  • Jakubowski, M., and Roberts, J. L. (1994). Processing of gonadotropin-releasing hormone gene transcripts in the rat brain.J. Biol. Chem. 269:4078–4083.

    PubMed  Google Scholar 

  • Karaviti, L. P., and Angelides, K. J. (1993). Expression of progesterone and dopamine receptors on GnRH neurons. Endocrine Society, Abstract No. 955.

  • Kepa, J. K., Wang, C., Neeley, C. I., Raynolds, M. V., Gordon, D. F., Wood, W. M., and Wierman, M. E. (1992). Structure of the rat gonadotropin releasing hormone (rGnRH) gene promoter and functional analysis in hypothalamic cells.Nucleic Acids Res. 20:1393–1399.

    PubMed  Google Scholar 

  • Kepa, J. K., Jacobsen, B. M., Boen, E. A., Takimoto, G., Edwards, D., and Wierman, M. E. (1994). Two sites in the proximal rat GnRH (rGnRH) promoter mediate negative regulation by progesterone. Endocrine Society, Abstract No. 1469.

  • Krsmanovic, L. Z., Stojilkovic, S. S., Merelli, F., Dufour, S. M., Virmani, M. A., and Catt, K. J. (1992). Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons.Proc. Natl. Acad. Sci. USA 89:8462–8466.

    PubMed  Google Scholar 

  • Mahachoklertwattana, P., Sanchez, J., Kaplan, S. L., and Grumbach, M. M. (1994). N-methyl-D-aspartate (NMDA) receptors mediate the release of gonadotropin-releasing hormone (GnRH) by NMDA in a hypothalamic GnRH neuronal cell line (GT1-1).Endocrinology 134:1023–1030.

    PubMed  Google Scholar 

  • Mason, A. J., Hayflick, J. S., Zoeller, R. T., Young, W. S., III, Phillips, H. S., Nikolics, K., and Seeburg, P. H. (1986). A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse.Science 234:1366–1371.

    PubMed  Google Scholar 

  • Maxwell, I. H., Harrison, G. S., Wood, W. M., and Maxwell, F. (1989). A DNA cassette containing a trimerized SV40 polyadenylation signal which efficiently blocks spurious plasmid-initiated transcription.Biotechniques 7:276–280.

    PubMed  Google Scholar 

  • Mellon, P. L., Windle, J. J., Goldsmith, P. C., Padula, C. A., Roberts, J. L., and Weiner, R. I. (1990). Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis.Neuron 5:1–10.

    PubMed  Google Scholar 

  • Milenkovic, L., D'Angelo, G., Kelly, P. A., and Weiner, R. A. (1994). Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors.Proc. Natl. Acad. Sci. USA 91:1244–1247.

    PubMed  Google Scholar 

  • Negro-Vilar, A., Conte, D., and Valenca, M. (1986). Transmembrane signals mediating neural peptide secretion: Role of protein kinase C activators and arachidonic acid metabolites in luteinizing hormone-releasing hormone secretion.Endocrinology 119:2796–2802.

    PubMed  Google Scholar 

  • Negro-Vilar, A., Valenca, M. M., and Culler, M. D. (1987). Transmembrane signals and extracellular messengers mediating LHRH and LH secretion.Adv. Exp. Med. Biol. 219: 85–108.

    PubMed  Google Scholar 

  • Ojeda, S. R., Urbanski, H. F., Katz, K. H., Costa, M. E., and Conn, P. M. (1986). Activation of two different but complimentary biochemical pathways stimulates release of hypothalamic luteinizing hormone-releasing hormone.Proc. Natl. Acad. Sci. USA 83:4932–4936.

    PubMed  Google Scholar 

  • Patriquin, E., Smith, E., and Radovick, S. (1994). Differential RNA splicing of the mouse pro-GnRH transcript in a neuronal cell line. Endrocrine Society, Abstract No. 1278.

  • Radovick, S., Wondisford, F. E., Nakayama, Y., Yamada, M., Cutler, G. B., Jr., and Weintraub, B. D. (1990). Isolation and characterization of the human gonadotropin-releasing hormone gene in the hypothalamus and placenta.Mol. Endocrinol. 4:476–480.

    PubMed  Google Scholar 

  • Radovick, S., Ticknor, C. M., Nakayama, Y., Notides, A. C., Rahman, A., Weintraub, B. D., Cutler, G. B., Jr., and Wondisford, F. E. (1991a). Evidence for direct estrogen regulation of the human gonadotropin-releasing hormone gene.J. Clin. Invest. 88:1649–1655.

    PubMed  Google Scholar 

  • Radovick, S., Wray, S., Lee, E., Nicols, D. K., Nakayama, Y., Weintraub, B. D., Westphal, H., Cutler, G. B., Jr., and Wondisford, F. E. (1991b). Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice.Proc. Natl. Acad. Sci. USA 88:3402–3406.

    PubMed  Google Scholar 

  • Seeburg, P. H., and Adelman, J. P. (1984). Characterization of cDNA for precursor of human luteinizing hormone releasing hormone.Nature 311:666–668.

    PubMed  Google Scholar 

  • Valenca, M. M., Conte, D., and Negro-Vilar, A. (1985). Diacylglycerol and phorbol esters enhance LHRH and prostaglandin E2 secretion from median eminence nerve terminals in vitro.Brain Res. Bull. 15:657–659.

    PubMed  Google Scholar 

  • Wetsel, W. C., Valenca, M. M., Merchenthaler, I., Liposits, Z., Lopez, F. J., Weiner, R. I., Mellon, P. L., and Negro-Vilar, A. (1992). Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons.Proc. Natl. Acad. Sci. USA 89:4149–4153.

    PubMed  Google Scholar 

  • Wetsel, W. C., Eraly, S. A., Whyte, D. B., and Mellon, P. L. (1993). Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons.Endocrinology 132:2360–2370.

    PubMed  Google Scholar 

  • Wierman, M. E., Kepa, J. K., Sun, W., Gordon, D. F., and Wood, W. M. (1992). Estrogen negatively regulates rat gonadotropin releasing hormone (rGnRH) promoter activity in transfected placental cells.Mol. Cell. Endocrinol. 86:1–10.

    PubMed  Google Scholar 

  • Zeng, Z., Dong, K., Yeo, T., and Roberts, J. (1994). Characterization of the regulatory element and factors responsible for PKC negative regulation of mouse GnRH gene transcription. Endocrine Society, Abstract No. 1474.

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Authors and Affiliations

  1. Department of Medicine, University of Colorado Health Science Center, and Research Service, Veterans Affairs Medical Center, 80220, Denver, Colorado

    Margaret E. Wierman, Jan M. Bruder & Jadwiga K. Kepa

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  1. Margaret E. Wierman
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  2. Jan M. Bruder
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  3. Jadwiga K. Kepa
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Wierman, M.E., Bruder, J.M. & Kepa, J.K. Regulation of gonadotropin-releasing hormone (GnRH) gene expression in hypothalamic neuronal cells. Cell Mol Neurobiol 15, 79–88 (1995). https://doi.org/10.1007/BF02069559

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  • DOI: https://doi.org/10.1007/BF02069559

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