Analyse der molekularen Mechanismen, die die Stabilität der neuromuskulären Synapse in Drosophila regulieren

在整个神经系统中，有证据表明，神经回路的完善和调节不仅受突触形成的驱动，还受先前功能突触连接的调节组装的驱动。在任何生物体的神经系统中，关于调节和实现突触稳定与解体的分子机制知之甚少。我们最近证明突触前谱蛋白是突触稳定所必需的。突触前谱蛋白骨架的缺失导致神经肌肉突触的解体、收缩和消除。在这里，我建议定义连接谱蛋白与突触质膜和肌动蛋白细胞骨架所需的分子网络。在其他系统中，如红细胞和上皮细胞，谱蛋白通过不同的接头蛋白与跨膜蛋白和肌动蛋白骨架相连。在上皮细胞中，spectrin可以通过接头蛋白锚蛋白与L1细胞粘附分子Neuroglian连接。还证明了接头分子内收蛋白调节亚膜谱-肌动蛋白网络的形成和稳定性。初步数据表明，内收蛋白和锚蛋白都存在于果蝇NMJ中。我将使用遗传，分子和电生理分析来解决这些基因是否对突触稳定性是必要的。

Throughout the nvervous system there is evidence that the refinement and modulation of neural circuitry is driven not only by synapse formation, but also by the regulated isassembly of previously functional synaptic connections. Very little is known about the molecular mechanisms that regulate and achieve synapse stability versus disassembly in the nervous system of any organism. We have recently demonstrated that presynaptic spectrin is necessary for synapse stabilization. Loss of the presynaptic spectrin skeleton leads to neuromuscular synapse disassembly, retraction and elimination. Here I propose to define the molecular network that is required to connect spectrin to both the synaptic plasma membrane and the actin cytoskeleton. In ohter systems such a erythrocytes and epithelial cells spectrin is linked to transmembrane proteins and the actin cytoskeleton via different adaptor proteins. In epithelial cells spectrin can be linked via the adaptor protein Ankyrin to the L1 cell adhesion molecule Neuroglian. It has also been demonstrated that the adaptor molecule Adducin regulates the formation and stability of the submembranous spectrin-actin network. Preliminary data demonstrates that both Adducin und Ankyrin are present at the Drosophila NMJ. I will use genetic, molecular and electrophysiological analyses to adress whether these genes are necessary for synapse stability.