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

Abstract

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 (ϩ/Ϫ) 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Unilateral 6-OHDA <i>th-fgfr1</i>(<i>tk-</i>) mouse model supports the role of FGFs in Parkinson’s disease and the effects of nicotine and L-DOPA on spontaneous motor impairments

“…Analysis of depletion of DA biomarkers in the striatum showed a trend towards increased loss of DA and DA metabolite content in the transgenic mice relative to controls (Figures 3(a)-(c)) and TH immunostaining in the striatum and SNc further substantiated strong unilateral nigrostriatal damage in th-fgfr1(tk-) mice ( Figure 4). These results are in agreement with previous findings of high susceptibility to 6-OHDA in mice with impaired FGF signaling [36].…”

“…Previous studies of FGF-2 KO mice showed an increased susceptibility of DA neurons to 6-OHDA [36]. To assess this possibility in th-fgfr1(tk) mice, we first analyzed rotational movement after administration of apomorphine in the Rotometer Test.…”

“…In human PD patients there was a reduction in the percentage of FGF-2 immunoreactive DA neurons relative to healthy subjects (12.7% FGF-2 positive DA neurons versus 82% FGF-2 positive DA neurons in control brains) [17]. Timmer and colleagues (2007) reported that in adult FGF-2 knockout mice with 6-hydroxydopamine (6-OHDA) lesions, significantly fewer DA neurons survived compared to non-lesioned controls [36].…”

ES cell-derived renewable and functional midbrain dopaminergic progenitors

“…Notably, previous studies of mDA NP proliferation mostly relied on animal system(s) or mixed primary cultures, sometimes resulting in conflicting observations. For example, even though bFGF is widely used as a mitogen for NPs (16), mDA NPs increased in bFGF KO mice, whereas mDA NPs decreased in bFGF-overexpressing transgenic mice (15,31). These unexpected results may be caused by multiple compensatory mechanisms in vivo.…”

How to improve the survival of the fetal ventral mesencephalic cell transplanted in Parkinson’s disease?

“…Besides GDNF and EPO, there are also some other trophic factors used to improve the survival of the grafts, including brain derived neurotrophic factor [30] , fibroblast growth factor (FGF) [31] , nerve growth factor (NGF) [32] and so on. Although studies performed in different laboratories have convincingly established that exposure of DA grafts to some trophic factors during storage prior to transplantation or repeated injection of trophic factors into the implantation site will improve the grafts survival efficaciously, the optimal factors for support of DA grafts should be further identified.…”