FACULTY

	Pamela Mellon, PhD in Molecular Biology, University of California, Berkeley, 1979 Professor of Reproductive Medicine and Neuroscience Division of Reproductive Endocrinology Secondary Appointments: Director of the Center for Reproductive Science and Medicine 9500 Gilman Drive Leichtag Biomedical Sciences Building, 3A14 office tel: (858) 534-1312 Fax: (858) 534-1438 Email: pmellon@ucsd.edu Lab Website: http://repro.ucsd.edu/Faculty/pmellon/default.htm
CV
Research Title
Vice-Chair for Research
Research Description
The brain controls the body’s physiology through neurohormones secreted from the hypothalamus. In particular, reproduction is regulated by the decapeptide gonadotropin-releasing hormone (GnRH). GnRH is produced by as few as 800 specialized neurons in the hypothalamus. Its function is to control release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. These hormones in turn control gametogenesis, puberty, menopause, menstrual cycles, and fertility. We study the regulation of these hormone genes at the molecular level both by hormones and neurotransmitters and throughout development. We use an integrated program of molecular approaches including: 1) Analysis in transgenic and knock-out mice; 2) Generation of novel pituitary and hypothalamic cell lines; 3) Investigation of the transcriptional regulatory proteins that control development, cellular identity, gene expression, and hormonal response; 4) Pulsatile secretion and circadian rhythms; and 5) Genomic approaches including DNA array analysis. Using targeted oncogenesis in transgenic mice, we have created a variety of cultured cell models for pituitary endocrine cells and hypothalamic neurons. The impact of the development of these models has been enormous, creating entirely new directions for molecular research in reproductive neuroendocrinology. The creation of a series of pituitary cell lines representing sequential stages in development within several of the anterior pituitary endocrine cell lineages has allowed us to significantly illuminate the developmental and hormonal regulation of hormone gene expression, synthesis and secretion. The creation of immortal hypothalamic GnRH neurons has facilitated rapid advances in understanding the roles of neurotransmitters and transcriptional regulators in hypothalamic function. For example, this model allowed the demonstration that the GnRH pulse generator is intrinsic to the GnRH neuron, since secretion is pulsatile in these clonal cells in culture. In addition to Dr. Mellon's own important contributions, researchers around the world are using her cultured cell models to study key issues in neuroendocrinology that were previously unapproachable. The impact of these model systems has produced a revolution in the approaches used to study the neuroendocrinology of reproduction.
Recent Publications
Belsham, D. D., Mellon, P. L. (2000). Transcription Factors Oct-1 and C/EBP beta are Involved in the Glutamate/Nitric Oxide/cyclic GMP-Mediated Repression of Gonadotropin-Releasing Hormone Gene Expression. Molecular Endocrinology 14, 212-228 Kelley, C. G., Lavorgna, G., Clark, M. E., Boncinelli, E., and Mellon, P. L. (2000). The Otx2 Homeoprotein Regulates Expression from the Gonadotropin-Releasing Hormone Proximal Promoter. Molecular Endocrinology 14, 1246-1256. Nelson, S. B., Lawson, M. A., Kelley, C. G., and Mellon, P. L. (2000). Neuron-specific Expression of the Rat Gonadotropin-Releasing Hormone Gene is Conferred by Interactions of a Defined Promoter Element with the Enhancer in GT1-7 Cells. Molecular Endocrinology 14, 1509-1522. Sosnowski, R., Mellon, P. L., Lawson, M. A. (2000). Activation of Translation in Pituitary Gonadotrope Cells by Gonadotropin-Releasing Hormone. Molecular Endocrinology 14, 1811-1819. 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. Liu, F., Austin, D. A., Mellon, P. L., Olefsky, J. M., Webster, N. J. G. (2002). GnRH Activates ERK1/2 Leading to the Induction of c-fos and LH Beta Protein Expression in LBetaT2 Cells. Molecular Endocrinology 16, 419-434. Lawson, M. A., MacConell, L. A., Kim, J., Powl, B. T., Nelson, S. B., Mellon, P. L. (2002). Neuron-Specific Expression In Vivo by Defined Transcription Regulatory Elements of the GnRH Gene. Endocrinology 143, 1404-1412. Vasilyev, V. V., Pernasetti, F., Rosenberg, S. B., Barsoum, M. J., Austin, D. A., Webster, N. J. G., Mellon, P. L. (2002). Transcriptional Activation of the Ovine Follicle-Stimulating Hormone-Beta Gene by Gonadotropin-Releasing Hormone Involves Multiple Signal Transduction Pathways. Endocrinology 143, 1651-1659. http://endo.endojournals.org/cgi/content/full/143/5/1651 Holley, S. J., Hall, S. B., Mellon, P. L. (2002). Complementary Expression of IGF-II and IGFBP-5 during Anterior Pituitary Development. Developmental Biology 244, 319-328. Arroyo, A., Pernasetti, F., Vasilyev, V. V., Amato, P., Yen, S. S. C., Mellon, P. L. (2002). A Unique Case of Combined Pituitary Hormone Deficiency Caused by a PROP1 Gene Mutation (R120C) Associated with Normal Height and Absent Puberty. Clinical Endocrinology 57, 283-291. Rosenberg, S. B., Mellon, P. L. (2002). An Otx-Related Homeodomain Protein Binds an LH Beta Promoter Element Important for Activation During Gonadotrope Maturation. Molecular Endocrinology 16, 1280-1298. http://mend.endojournals.org/cgi/content/full/16/6/1280 Vasilyev, V. V., Lawson, M. A., DiPaolo, D., Webster, N. J. G., Mellon, P. L. (2002). Different Signaling Pathways Control Acute Induction versus Long-Term Repression of LH Beta Transcription by GnRH. Endocrinology 143, 3414-3426. http://endo.endojournals.org/cgi/content/full/143/9/3414 Liu, F., Usui, I., Evans, L. G., Austin, D. A., Mellon, P. L., Olefsky, J. M., Webster, N. J. G. (2002). Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LBetaT2 Cells. Journal of Biological Chemistry 277, 32099-32108. http://www.jbc.org/cgi/content/full/277/35/32099 Kelley, C. G., Givens, M. L., Rave-Harel, N., Nelson, S. B., Anderson, S., Mellon, P. L. (2002). Neuron-Restricted Expression of the Rat Gonadotropin-Releasing Hormone Gene is Conferred by a Cell-Specific Protein Complex that Binds Repeated CAATT Elements. Molecular Endocrinology 16, 2413-2425. http://mend.endojournals.org/cgi/content/full/16/11/2413 Pernasetti, F., Spady, T .J., Hall, S. B., Rosenberg, S. B., Givens, M. L., Anderson, S., Paulus, M., Miller, W. L., and Mellon, P. L. (2003). Pituitary Tumorigenesis Targeted by the Ovine Follicle-Stimulating Hormone Beta-Subunit Gene Regulatory Region in Transgenic Mice. Molecular and Cellular Endocrinology 203, 169-183. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12782413 Jacobs, S. B. R., Coss, D., McGillivray, S. M., Mellon, P. L. (2003). Nuclear Factor Y and Steroidogenic Factor 1 Physically and Functionally Interact to Contribute to Cell-Specific Expression of the Mouse Follicle-Stimulating Hormone-Beta Gene. Molecular Endocrinology 17, 1470-1483. http://mend.endojournals.org/cgi/content/full/17/8/1470 Chappell, P. E., White, R. S., Mellon, P. L. (2003). Circadian Gene Expression Regulates Pulsatile Gonadotropin-Releasing Hormone (GnRH) Secretory Patterns in the Hypothalamic GnRH-Secreting GT1-7 Cell Line. Journal of Neuroscience 23, 11202-11213. http://www.jneurosci.org/cgi/content/full/23/35/11202 Coss, D., Jacobs, S. B. R., Bender, C. E., Mellon, P. L. (2004). A Novel AP-1 Site is Critical for Maximal Induction of the Follicle-Stimulating Hormone Beta Gene by Gonadotropin-Releasing Hormone. Journal of Biological Chemistry 279, 152-162. http://www.jbc.org/cgi/content/full/279/1/152 Spady, T. J., Shayya, R., Thackray, V. G., Ehrensberger, L., Bailey, J. S., Mellon, P. L. (2004). Androgen Regulates Follicle-Stimulating Hormone-Beta Gene Expression in an Activin-Dependent Manner in Immortalized Gonadotropes. Molecular Endocrinology 18, 925-940. http://mend.endojournals.org/cgi/content/full/18/4/925 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. http://mend.endojournals.org/cgi/content/full/18/5/1158 Rave-Harel, N., Givens,* M. L., Nelson,* S. B., Duong, H. A., Coss, D., Clark, M. E., Hall, S. B., Kamps, M. P., and Mellon, P. L. (2004). TALE Homeodomain Proteins Regulate Gonadotropin-Releasing Hormone Gene Expression Independently and Via Interactions with Oct-1. Journal of Biological Chemistry 279, 30287-30297. equivalent contributions http://www.jbc.org/cgi/content/full/279/29/30287 Givens, M. L., Kurotani,* R., Rave-Harel, N., Miller, N. L. G., Mellon, P. L. (2004). Phylogenetic Footprinting Reveals Evolutionarily Conserved Regions of the Gonadotropin-Releasing Hormone Gene that Enhance Cell-Specific Expression. Molecular Endocrinology 18, 2950-2966. equivalent contributions http://mend.endojournals.org/cgi/content/full/18/12/2950 McGillivray, S. M., Bailey,* J. S., Ramezani, R., Kirkwood, B. J., Mellon, P. L. (2005). Mouse GnRH Receptor Gene Expression is Mediated by the LHX3 Homeodomain Protein. Endocrinology 146, 2180-2185. equivalent contributions http://endo.endojournals.org/cgi/content/full/146/5/2180 Givens, M. L., Rave-Harel, N., Goonewardena, V. D., Kurotani, R., Berdy, S. E., Swan, C., Rubenstein, J. L. R., Robert,* B., Mellon, P. L. (2005). Developmental Regulation of Gonadotropin-Releasing Hormone Gene Expression by the Msx and Dlx Homeodomain Protein Families. Journal of Biological Chemistry 280, 19156-19165. equivalent contributions http://www.jbc.org/cgi/reprint/280/19/19156 Rave-Harel, N., Miller, N. L. G., Givens,* M. L., Mellon, P. L. (2005). The Groucho-Related Gene Family Regulates the Gonadotropin-releasing Hormone Gene through Interaction with the Homeodomain Proteins Oct 1 and Msx-1. Journal of Biological Chemistry 280, 30975-30983. equivalent contributions http://www.jbc.org/cgi/reprint/280/35/30975 Coss, D., Thackray, V. G., Deng, C. X., Mellon, P. L. (2005). Activin Regulates Luteinizing Hormone Beta-Subunit Gene Expression through Smad-binding and Homeobox Elements. Molecular Endocrinology 19, 2610-2623. http://mend.endojournals.org/cgi/content/full/19/10/2610 Tang, Q., Mazur, M., Mellon, P.L. (2005). The Protein Kinase C Pathway Acts Through Multiple Transcription Factors to Repress Gonadotropin-Releasing Hormone Gene Expression in Hypothalamic GT1-7 Neuronal Cells. Molecular Endocrinology 19, 2769-2779. http://mend.endojournals.org/cgi/content/full/19/11/2769 Thackray, V. G., McGillivray,* S. M., Mellon, P. L. (2006). Androgens, Progestins and Glucocorticoids Induce Follicle-Stimulating Hormone Beta-Subunit Gene Expression at the Level of the Gonadotrope. Molecular Endocrinology 20, 2062-2079. equivalent contributions http://mend.endojournals.org/cgi/content/full/20/9/2062 Zhang, H., Bailey, J. S., Coss, D., Lin, B., Tsutsumi, R., Lawson, M.A., Mellon, P. L., Webster, N. J. G. (2006). Activin Modulates the Transcriptional Response of LBetaT2 Cells to GnRH and Alters Cellular Proliferation. Molecular Endocrinology 20, 2909-2930. http://mend.endojournals.org/cgi/content/full/20/11/2909 McGillivray, S. M., Thackray, V. G., Coss, D., Mellon, P. L. (2007). Activin and Glucocorticoids Synergistically Activate Follicle-Stimulating Hormone Beta-Subunit Gene Expression in the Immortalized LBetaT2 Gonadotrope Cell Line. Endocrinology 148, 762-773. http://endo.endojournals.org/cgi/content/full/148/2/762 Sasson, R., Dearth, R. K., White, R. S., Chappell, P. E., Mellon, P. L. (2007). Orexin A Induces GnRH Gene Expression and Secretion from GT1-7 Hypothalamic GnRH Neurons. Neuroendocrinology 84, 353-363. http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000098333 Lawson, M. A., Tsutsumi, R., Zhang, H., Talukdar, I., Butler, B. K., Santos, S. J., Mellon, P. L., Webster, N. J. G. (2007). Pulse Sensitivity of the LH Beta Promoter is Determined by a Negative Feedback Loop Involving Egr1 and Nab1/2. Molecular Endocrinology 21, 1175 - 1191. http://mend.endojournals.org/cgi/content/full/21/5/1175 Coss, D., Hand, C. M., Yaphockun, K. K. J., Ely, H. A., Mellon, P. L. 2007 p38 MAPK is Critical for Synergistic Induction of the FSH Beta Gene by GnRH and Activin through Augmentation of c-Fos Induction and Smad Phosphorylation. Molecular Endocrinology, e-pub before print http://mend.endojournals.org/cgi/rapidpdf/me.2007-0247v1 Pitteloud N, Zhang* C, Pignatelli D, Li J-D, Raivio T, Cole L, Plummer L, Dickson-Jackobson EE, Mellon PL, Zhou* Q-Y, Crowley* WF Jr 2007 Loss-of-function mutations in the Prokineticin 2 gene cause Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism. Proc Natl Acad Sci USA 104:17447-17452. PMC2077276 Coss D, Hand CM, Yaphockun KKJ, Ely HA, Mellon PL 2007 p38 MAPK is critical for synergistic induction of the FSHâ gene by GnRH and activin through augmentation of c-Fos induction and Smad phosphorylation. Mol Endocrinol 12:3071-3086. Lu M, Tang Q, Olefsky JM, Mellon PL, Webster NJG 2008 Adiponectin activates AMPK and decreases luteinizing hormone secretion in LâT2 gonadotropes. Mol Endocrinol 22:760-771. PMC2262174 McMahon HE, Hashimoto O, Mellon PL, Shimasaki S 2008 Oocyte-specific over-expression of mouse BMP-15 leads to accelerated folliculogenesis and an early onset of acyclicity in transgenic mice. Endocrinology 149:812-817. PMC2408818 Thackray VG, Mellon PL 2008 Synergistic induction of follicle-stimulating hormone â-subunit gene expression by gonadal steroid hormone receptors and smad proteins. Endocrinology 149:1091-1102. PMC2275352 Sasson* R, Luu* SH, Thackray VG, Mellon PL 2008 Glucocorticoids induce human glycoprotein hormone alpha-subunit gene expression in the gonadotrope. Endocrinology 149:3643-3655. PMC2453092 Cherrington* BD, Bailey* JS, Diaz AL, Mellon PL 2008 NeuroD1 and Mash1 temporally regulate GnRH receptor gene expression in immortalized mouse gonadotrope cells. Mol Cell Endocrinol 295:106-114. PMC2640340 Avelino-Cruz JE, Flores A, Mellon PL, Felix R, Monjaraz E 2008 Leptin increases L-type Ca2+ channel expression and GnRH-stimulated LH release in LâT2 gonadotropes. Mol Cell Endocrinol 298:57-65. PMC2659688 Miller NLG, Wevrick R, Mellon PL 2009 Necdin, a Prader-Willi Syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development. Hum Mol Genet 18:248-260. PMC2638776 Thackray VG, Hunnicutt JL, Memon AK, Ghochani Y, Mellon PL 2009 Progesterone inhibits basal and GnRH induction of luteinizing hormone â-subunit gene expression. Endocrinology 150:2395-2403. PMC2671912 Larder R, Mellon PL 2009 Otx2 induction of the gonadotropin-releasing hormone promoter is modulated by direct interactions with Grg co-repressors. J Biol Chem 284:16966-16978.

Page last updated: July 14, 2009

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