Preferential neurotrophic activity of fibroblast growth factor-20 for dopaminergic neurons through fibroblast growth factor receptor-1c.
Degeneration of dopaminergic neurons of the substantia nigra causes Parkinson's disease. Therefore, neurotrophic factors for dopaminergic neurons are of substantial clinical interest. Fibroblast growth factor (FGF)-20 preferentially expressed in the substantia nigra pars compacta (SNPC) of the rat brain significantly enhanced the survival of midbrain dopaminergic neurons. Here we examined the mechanism of action of FGF-20 on dopaminergic neurons. FGF-20 slightly enhanced the survival of total neurons of the midbrain, indicating that it preferentially enhanced the survival of dopaminergic neurons. FGF receptor (FGFR)-1c was found to be expressed abundantly in dopaminergic neurons in the SNPC but at much lower levels in neurons of other midbrain regions by in situ hybridization. FGF-20 was also found to bind FGFR-1c with high affinity with the BIAcore system. Furthermore, FGF-20 activated the mitogen-activated protein kinase (MAPK) pathway, which is the major intracellular signaling pathway of FGFs. Both the FGFR-1 inhibitor SU5402 and the MAPK pathway inhibitor PD98059 also significantly inhibited the activation of the MAPK pathway by FGF-20 and the neurotrophic activity of FGF-20. The present findings indicate that the activation of the MAPK pathway by FGF-20 signaling through FGFR-1c plays important roles in the survival of dopaminergic neurons in the SNPC.
Ohmachi
Shigeki
S
Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan.
Mikami
Tadahisa
T
Konishi
Morichika
M
Miyake
Ayumi
A
Itoh
Nobuyuki
N
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D017403:In Situ Hybridization; D008636:Mesencephalon / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; C498813:Fgf20 protein, rat; D005419:Flavonoids; D011758:Pyrroles; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402; D005346:Fibroblast Growth Factors; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D004298:Dopamine