Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra, and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion.
Basic fibroblast growth factor (FGF-2) is involved in the development and maintenance of the nervous system. Exogenous administration of FGF-2 increased dopaminergic (DA) graft survival in different animal models of Parkinson's disease. To study the physiological function of the endogenous FGF-2 system, we analyzed the nigrostriatal system of mice lacking FGF-2, mice overexpressing FGF-2, and FGF-receptor-3 (FGFR3)-deficient mice both after development and after 6-hydroxydopamine lesion. FGFR3-deficient mice (+/-) displayed a reduced number of DA neurons compared with the respective wild type. Whereas absence of FGF-2 led to significantly increased numbers of DA neurons, enhanced amount of the growth factor in mice overexpressing FGF-2 resulted in less tyrosine hydroxylase expression and a reduced DA cell density. The volumes of the substantia nigra were enlarged in both FGF-2(-/-) and in FGF-2 transgenic mice, suggesting an important role of FGF-2 for the establishment of the proper number of DA neurons and a normal sized substantia nigra during development. In a second set of experiments, the putative relevance of endogenous FGF-2 after neurotoxin application was investigated regarding the number of rescued DA neurons after partial 6-OHDA lesion. Interestingly, the results after lesion were directly opposed to the results after development: significantly less DA neurons survived in FGF-2(-/-) mice compared with wild-type mice. Together, the results indicate that FGFR3 is crucially involved in regulating the number of DA neurons. The lack of FGF-2 seems to be (over)compensated during development, but, after lesion, compensation mechanisms fail. The transgenic mice showed that endogenous FGF-2 protects DA neurons from 6-OHDA neurotoxicity.
Timmer
Marco
M
Department of Neuroanatomy, Hannover Medical School, Center for Systems Neuroscience Hannover, 30625 Hannover, Germany.
Cesnulevicius
Konstantin
K
Winkler
Christian
C
Kolb
Julia
J
Lipokatic-Takacs
Esther
E
Jungnickel
Julia
J
Grothe
Claudia
C
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D016627:Oxidopamine; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis* / Q000172:deficiency; D013378:Substantia Nigra / Q000254:growth & development* / Q000378:metabolism*
D016222:Fibroblast Growth Factor 2; D016627:Oxidopamine; D051498:Receptor, Fibroblast Growth Factor, Type 3; D004298:Dopamine