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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.
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