Fibroblast growth factor 2 regulates dopaminergic neuron development in vivo

Abstract

J. Neurochem. (2012) 122, 94–105. Abstract Fibroblast growth factor 2 (FGF‐2) is a neurotrophic factor participating in regulation of proliferation, differentiation, apoptosis and neuroprotection in the central nervous system. With regard to dopaminergic (DA) neurons of substantia nigra pars compacta (SNpc), which degenerate in Parkinson’s disease, FGF‐2 improves survival of mature DA neurons in vivo and regulates expansion of DA progenitors in vitro. To address the physiological role of FGF‐2 in SNpc development, embryonic (E14.5), newborn (P0) and juvenile (P28) FGF‐2‐deficient mice were investigated. Stereological quantification of DA neurons identified normal numbers in the ventral tegmental area, whereas the SNpc of FGF‐2‐deficient mice displayed a 35% increase of DA neurons at P0 and P28, but not at earlier stage E14.5. Examination of DA marker gene expression by quantitative RT‐PCR and in situ hybridization revealed a normal patterning of embryonic ventral mesencephalon. However, an increase of proliferating Lmx1a DA progenitors in the subventricular zone of the ventral mesencephalon of FGF‐2‐deficient embryos indicated altered cell cycle progression of neuronal progenitors. Increased levels of nuclear FgfR1 in E14.5 FGF‐2‐deficient mice suggest alterations of integrative nuclear FgfR1 signaling (INFS). In summary, FGF‐2 restricts SNpc DA neurogenesis in vivo during late stages of embryonic development.

Cooperation of Nuclear Fibroblast Growth Factor Receptor 1 and Nurr1 Offers New Interactive Mechanism in Postmitotic Development of Mesencephalic Dopaminergic Neurons

“…Furthermore, disruption of FGFR1 signaling in developing postmitotic mDA neurons impairs their maturation and function (3), indicating a direct role of nuclear FGFR1 in postmitotic mDA neuronal development. Interestingly, FGF-2-deficient mice display an increase of mDA neurons expressing nuclear FGFR1 in the substantia nigra during terminal differentiation (60). The specific role of nuclear FGFR1 remains to be further elucidated in this system.…”

The role of fibroblast growth factor 2 in drug addiction

“…For example, DAergic cell death was increased in FGF2 knockout mice with 6‐OHDA‐lesion, but was decreased in FGF2 overexpressing mice, compared to wild‐type controls (Timmer et al ., ). Interestingly, mice overexpressing FGF2 had fewer DAergic neurons, whereas FGF2 knockout mice had an increased number of DAergic neurons (Timmer et al ., ; Ratzka et al ., ), increased striatum volume (Rumpel et al ., ), and increased DAergic innervation from the midbrain to the striatum (Baron et al ., ; Rumpel et al ., ). It is possible that these apparent paradoxical findings were due to compensative mechanisms by other FGF‐family ligands (Timmer et al ., ; Baron et al ., ; Ratzka et al ., ).…”

“…It is possible that these apparent paradoxical findings were due to compensative mechanisms by other FGF‐family ligands (Timmer et al ., ; Baron et al ., ; Ratzka et al ., ). This overcompensation could have led to increased proliferation of DA precursors during the late stages of embryonic development, as well as reduced apoptotic bodies in newborn FGF2 knockout mice (Ratzka et al ., ). Together, these findings suggest that Fgf2 deletion results in abnormal nigrostriatal development and reduced protection of DAergic neurons in adulthood.…”

Interaction between cholecystokinin and the fibroblast growth factor system in the ventral tegmental area of selectively bred high- and low-responder rats

“…Given the positive correlation between FGF-R1 and CCK transcript levels observed in the VTA of bHR rats, the increase of FGF-R1 gene expression is expected to influence their vulnerability to psychostimulants (Turner et al, 2008a). Although it is possible that other FGF family members (e.g., FGF1) may be acting at the high-affinity receptor FGF-R1 (Coutts and Gallagher, 1995), FGF-R1 function in midbrain dopaminergic neurons specifically relies on the FGF2 neurotransmission (Beck, 1994; Gonzalez et al, 1995; Klejbor et al, 2006; Ratzka et al, 2012). Moreover, we present evidence indicating that FGF-R1 and CCK are colocalized in some VTAr neurons (Fig.C), supporting the direct actions of FGF2 treatment on CCK neurons, and potentially dopamine, in this region.…”