Das FGF System und dopaminerge Neurone

成纤维细胞生长因子2是一种与中脑多巴胺能神经元相关的神经营养因子，其变性或发育异常分别与帕金森病和精神分裂症有关。已知成纤维细胞生长因子-2调节黑质致密部(SNPC)的充分发育，并保护成年MDA神经元免受神经毒性作用。我们先前的研究表明，尽管在体外，成纤维细胞生长因子-2被认为是一种有效的丙二醛前体有丝分裂原，但与野生型相比，成纤维细胞生长因子-2基因缺陷的小鼠在SNPC中发育出更多的丙二醛神经元。在过去的大时期，我们发现这种表型是在胚胎发育后期(E14.5-P0)的黑质中特有的，这似乎是两个改变的生理过程的结果。首先，我们发现，在成纤维细胞生长因子-2缺乏的VM中，Lmx1a阳性的MDA前体细胞在分化后期(E14.5)增强了向室下区的过渡，而脑室区的自我更新神经前体细胞却没有大量耗尽。此外，我们还发现E14.5 FGF2缺陷小鼠腹侧中脑细胞核内FGFR1的聚集增加，并且核聚集与VM细胞的进行性分化有关。此外，核FGFR1与Nurr1在功能上相互作用，Nurr1是指导丙二醛表型的关键转录因子。因此，我们认为由于成纤维细胞生长因子-2的缺失，成纤维细胞生长因子信号的失衡导致神经发生的增加或延长，这反映在核FGFR1信号的增加与Nurr1的协同作用上。其次，我们发现新生(P0)FGF2缺陷小鼠SNPC中个体源性神经细胞死亡减少。我们还在器官类型外植体共培养中表明，在VM和前脑中，成纤维细胞生长因子-2信号对于足够的黑质纹状体通路的形成是必要的。在这里，成纤维细胞生长因子-2似乎通过一个复杂的信号网络影响适当的靶神经支配，该网络调节通路并诱导错误连接的神经元中的个体细胞死亡。结论是，丢失成纤维细胞生长因子-2似乎导致SNPC的发育性增生，并可能导致基底节控制不足，这可能是先前描述的应激诱导的多动行为表型与DA传递增强的原因。因此，在正在进行的研究中，我们将重点放在两个已识别和基本表征的改变的生理过程上，即成纤维细胞生长因子-2的早期和晚期作用，并旨在分离不同的成纤维细胞生长因子-2亚型的空间和时间特性。对单个成纤维细胞生长因子-2亚型在自我更新和神经发生平衡以及黑质纹状体通路形成方面的分子和细胞机制的详细识别，可能会影响我们对神经元发育的整体认识，以及对帕金森病和精神分裂症等丙二醛相关疾病的新治疗策略的理解和开发。

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.