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.
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.
Department of Integrative Physiology and the Center for Neuroscience, University of Colorado, 114 Clare Small, Boulder, Colorado 80309-0354, USA. pei-san.tsai@colorado.edu
Pei-San
PS
Tsai
Suzanne M
SM
Moenter
Hector R
HR
Postigo
Mohammed
M
El Majdoubi
Toni R
TR
Pak
John C
JC
Gill
Sreenivasan
S
Paruthiyil
Sabine
S
Werner
Richard I
RI
Weiner
D000818:Animals; D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival; D018076:DNA, Complementary / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D018076:DNA, Complementary; D017468:Receptors, Fibroblast Growth Factor; D007987:Gonadotropin-Releasing Hormone; D005346:Fibroblast Growth Factors