Das FGF System und dopaminerge Neurone

• Applicant: Professorin Dr. Claudia Grothe
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2008 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 84845811

Fibroblast growth factor 2 (FGF-2) is a relevant neurotrophic factor for mesencephalic dopaminergic (mDA) neurons, whose degeneration or abnormal development is associated with Parkinsons disease and Schizophrenia, respectively. FGF-2 is known to regulate the adequate development of substantia nigra pars compacta (SNpc) and to protect the adult mDA neurons from neurotoxic effects. We showed previously that, paradoxically, FGF-2 deficient mice develop more mDA neurons in the SNpc than wild type, although FGF-2 is considered as a potent mitogen for mDA precursors in vitro. In the past grand period we showed that the phenotype develops specifically in the substantia nigra during late embryogenesis (E14.5 - P0), which seems to be a result of two altered physiological processes. First, we found in FGF-2 deficient VM an enhanced transition of Lmx1a-positive mDA precursors into the subventricular zone without a substantial depletion of self-renewing neural progenitors in the ventricular zone during late differentiation phase (E14.5). Additionally, we found an increased accumulation of FGFR1 in the nucleus of ventral mesencephalic cells of E14.5 FGF-2 deficient mice, and showed a correlation between nuclear accumulation and progressing differentiation of VM cells. Further, nuclear FGFR1 interacts functionally with Nurr1, the key transcription factor instructing the mDA phenotype. Therefore, we propose that due to FGF-2 loss the disbalanced FGF-signalling results in an increased or prolonged neurogenesis, which is reflected in increased nuclear FGFR1 signalling in cooperation with Nurr1. Second, we found a decreased ontogenic neuronal cell death in the SNpc of newborn (P0) FGF-2 deficient mice. We also show in organotypic explant cocultures that FGF-2 signalling is necessary in both VM and forebrain for an adequate nigrostriatal pathway formation. Here, FGF-2 seems to influence the adequate target innervation via an intricate signalling network, which regulates pathfinding and induces the ontogenic cell death in the wrongly wired neurons. Concluding, the loss of FGF-2 seems to cause a developmental hyperplasia of SNpc and may result in an inadequate basal ganglia control, which might be causative for the previously described stress induced hyperactive behavioural phenotype with enhanced DA transmission. Thus, in the ongoing study we focus on the two identified and basically characterized altered physiological processes, the early and late roles of FGF-2, and aim to segregate the spatial and temporal properties of the different FGF-2 isoforms. The detailed identification of the molecular and cellular mechanisms of the single FGF-2 isoforms with regard to the balance of self-renewal and neurogenesis, and nigrostriatal pathway formation could have impact on our overall knowledge on neuronal development and, in addition, on understanding and development of new therapeutic strategies of mDA-related diseases like Parkinsons disease and Schizophrenia.

• DFG Programme: Research Grants