This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsai, P.-S. Articles by Weiner, R. I. Search for Related Content PubMed PubMed Citation Articles by Tsai, P.-S. Articles by Weiner, R. I.

Targeted Expression of a Dominant-Negative Fibroblast Growth Factor (FGF) Receptor in Gonadotropin-Releasing Hormone (GnRH) Neurons Reduces FGF Responsiveness and the Size of GnRH Neuronal Population

Department of Integrative Physiology and the Center for Neuroscience (P.-S.T., T.R.P., J.C.G.), University of Colorado, Boulder, Colorado 80309-0354; Departments of Internal Medicine and Cell Biology (S.M.M.), University of Virginia, Charlottesville, Virginia 22908; Department of Physiology and Neurobiology (H.R.P.), University of Connecticut, Storrs, Connecticut 06269-4156; Department of Obstetrics and Gynecology and Reproductive Sciences (M.E.M., S.P., R.I.W.), University of California, San Francisco, California 94143-0556; and Institute of Cell Biology (S.W.), Department of Biology, ETH Zürich, CH-8093 Zürich, Switzerland

Address all correspondence and requests for reprints to: Pei-San Tsai, Department of Integrative Physiology, 114 Clare Small, University of Colorado, Boulder, Colorado 80309-0354. E-mail: pei-san.tsai{at}colorado.edu.

Increasing evidence suggests that fibroblast growth factors (FGFs) are neurotrophic in GnRH neurons. However, the extent to which FGFs are involved in establishing a functional GnRH system in the whole organism has not been investigated. In this study, transgenic mice with the expression of a dominant-negative FGF receptor mutant (FGFRm) targeted to GnRH neurons were generated to examine the consequence of disrupted FGF signaling on the formation of the GnRH system. To first test the effectiveness of this strategy, GT1 cells, a GnRH neuronal cell line, were stably transfected with FGFRm. The transfected cells showed attenuated neurite outgrowth, diminished FGF-2 responsiveness in a cell survival assay, and blunted activation of the signaling pathway in response to FGF-2. Transgenic mice expressing FGFRm in a GnRH neuron-specific manner exhibited a 30% reduction in GnRH neuron number, but the anatomical distribution of GnRH neurons was unaltered. Although these mice were initially fertile, they displayed several reproductive defects, including delayed puberty, reduced litter size, and early reproductive senescence. Overall, our results are the first to show, at the level of the organism, that FGFs are one of the important components involved in the formation and maintenance of the GnRH system.

This article has been cited by other articles:

				W. C. J. Chung, S. S. Moyle, and P.-S. Tsai Fibroblast Growth Factor 8 Signaling through Fibroblast Growth Factor Receptor 1 Is Required for the Emergence of Gonadotropin-Releasing Hormone Neurons Endocrinology, October 1, 2008; 149(10): 4997 - 5003. [Abstract] [Full Text] [PDF]

				J. C. Gill, B. Wadas, P. Chen, W. Portillo, A. Reyna, E. Jorgensen, S. Mani, G. A. Schwarting, S. M. Moenter, S. Tobet, et al. The Gonadotropin-Releasing Hormone (GnRH) Neuronal Population Is Normal in Size and Distribution in GnRH-Deficient and GnRH Receptor-Mutant Hypogonadal Mice Endocrinology, September 1, 2008; 149(9): 4596 - 4604. [Abstract] [Full Text] [PDF]

				T. Raivio, J. Falardeau, A. Dwyer, R. Quinton, F. J. Hayes, V. A. Hughes, L. W. Cole, S. H. Pearce, H. Lee, P. Boepple, et al. Reversal of Idiopathic Hypogonadotropic Hypogonadism N. Engl. J. Med., August 30, 2007; 357(9): 863 - 873. [Abstract] [Full Text] [PDF]

				X. Zhu, A. S. Gleiberman, and M. G. Rosenfeld Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks Physiol Rev, July 1, 2007; 87(3): 933 - 963. [Abstract] [Full Text] [PDF]

				N. Xu, Y. Qin, R. H. Reindollar, S. P. T. Tho, P. G. McDonough, and L. C. Layman A Mutation in the Fibroblast Growth Factor Receptor 1 Gene Causes Fully Penetrant Normosmic Isolated Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 1155 - 1158. [Abstract] [Full Text] [PDF]

				N. Chattopadhyay, K.-H. Jeong, S. Yano, S. Huang, J. L. Pang, X. Ren, E. Terwilliger, U. B. Kaiser, P. M. Vassilev, M. R. Pollak, et al. Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E523 - E532. [Abstract] [Full Text] [PDF]

				N. Pitteloud, J. S. Acierno Jr., A. Meysing, A. V. Eliseenkova, J. Ma, O. A. Ibrahimi, D. L. Metzger, F. J. Hayes, A. A. Dwyer, V. A. Hughes, et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism PNAS, April 18, 2006; 103(16): 6281 - 6286. [Abstract] [Full Text] [PDF]

				S. A. Tobet and G. A. Schwarting Minireview: Recent Progress in Gonadotropin-Releasing Hormone Neuronal Migration Endocrinology, March 1, 2006; 147(3): 1159 - 1165. [Abstract] [Full Text] [PDF]

				J. C. Gill and P.-S. Tsai Expression of a Dominant Negative FGF Receptor in Developing GNRH1 Neurons Disrupts Axon Outgrowth and Targeting to the Median Eminence Biol Reprod, March 1, 2006; 74(3): 463 - 472. [Abstract] [Full Text] [PDF]

				N. Pitteloud, J. S. Acierno Jr., A. U. Meysing, A. A. Dwyer, F. J. Hayes, and W. F. Crowley Jr. Reversible Kallmann Syndrome, Delayed Puberty, and Isolated Anosmia Occurring in a Single Family with a Mutation in the Fibroblast Growth Factor Receptor 1 Gene J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1317 - 1322. [Abstract] [Full Text] [PDF]