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The Journal of Neuroscience, January 17, 2007, 27(3):459-471; doi:10.1523/JNEUROSCI.4493-06.2007

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Development/Plasticity/Repair
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

Marco Timmer,¹ Konstantin Cesnulevicius,¹ Christian Winkler,² Julia Kolb,¹ Esther Lipokatic-Takacs,¹ Julia Jungnickel,¹ and Claudia Grothe¹

Departments of ¹Neuroanatomy and ²Neurology, Hannover Medical School, Center for Systems Neuroscience Hannover, 30625 Hannover, Germany

Correspondence should be addressed to Prof. Dr. Claudia Grothe, Hannover Medical School, Department of Neuroanatomy, Center of Anatomy, OE 4140, Carl-Neuberg-Strasse 1, 30623 Hannover, Germany. Email: grothe.claudia{at}mh-hannover.de

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.

Key words: basic fibroblast growth factor; midbrain; mutant mice; Parkinson's disease; stereology; substantia nigra; terminal 6-OHDA lesion

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Received July 31, 2006; revised Nov. 30, 2006; accepted Dec. 4, 2006.

Correspondence should be addressed to Prof. Dr. Claudia Grothe, Hannover Medical School, Department of Neuroanatomy, Center of Anatomy, OE 4140, Carl-Neuberg-Strasse 1, 30623 Hannover, Germany. Email: grothe.claudia{at}mh-hannover.de

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