Das FGF System und dopaminerge Neurone

FGF 系统和多巴胺能神经元

• 批准号: 84845811
• 负责人: Professorin Dr. Claudia Grothe
• 金额: --
• 依托单位: Institut für Neuroanatomie und Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/84845811?language=en
• 关键词: Das; FGF; System; und; dopaminerge

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.

成纤维细胞生长因子2（FGF-2）是中脑多巴胺能（mDA）神经元的相关神经营养因子，其变性或异常发育分别与帕金森病和精神分裂症相关。已知FGF-2调节黑质腹侧部（SNpc）的充分发育并保护成年mDA神经元免受神经毒性作用。我们以前表明，自相矛盾的是，FGF-2缺陷型小鼠在SNpc中比野生型发育更多的mDA神经元，尽管FGF-2被认为是体外mDA前体的有效有丝分裂原。在过去的大时期，我们表明，表型发展特别是在黑质在胚胎发育后期（E14.5-P0），这似乎是两个改变的生理过程的结果。首先，我们发现在FGF-2缺陷VM增强过渡Lmx1a阳性mDA前体进入脑室下区，而没有大量消耗自我更新的神经祖细胞在脑室区在分化后期（E14.5）。此外，我们发现E14.5 FGF-2缺陷小鼠腹侧中脑细胞核中FGFR1的积累增加，并显示核积累与VM细胞的进展分化之间的相关性。此外，核FGFR1在功能上与Nurr1相互作用，Nurr1是指导mDA表型的关键转录因子。因此，我们提出，由于FGF-2的损失，不平衡的FGF信号导致增加或延长的神经发生，这反映在增加的核FGFR1信号与Nurr1合作。第二，我们发现新生（P0）FGF-2缺陷小鼠的SNpc中个体发生性神经元细胞死亡减少。我们还表明，在器官型外植体共培养，FGF-2信号是必要的VM和前脑足够的黑质纹状体通路的形成。在这里，FGF-2似乎通过一个复杂的信号网络影响适当的靶神经支配，该信号网络调节寻路并诱导错误连接的神经元中的个体发生性细胞死亡。总之，FGF-2的缺失似乎导致SNpc的发育性增生，并可能导致基底神经节控制不足，这可能是先前描述的具有增强的DA传递的应激诱导的多动行为表型的原因。因此，在正在进行的研究中，我们专注于两个确定的和基本特征的改变生理过程，FGF-2的早期和晚期作用，并旨在分离不同的FGF-2亚型的空间和时间特性。单个FGF-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鉴定可能会影响我们对神经元发育的整体知识，此外，还可能影响对mDA相关疾病（如帕金森病和精神分裂症）的新治疗策略的理解和开发。