Genetic Analysis of Axonal Transport in Synaptogenesis

描述(申请人提供)：为了组装新的突触，生长中的轴突需要分子来稳定早期接触，改变轴突的形态，并在两个细胞之间建立功能连接。这些分子是在细胞体中合成的，必须沿着轴突向下运输。事实上，突触构建块的运输对突触发生至关重要，可能会受到密切的调控。它对修改成人大脑中的突触也可能是至关重要的。 为了最终了解这些马达在突触发生中的特异性和调控，我们建议使用果蝇遗传学来研究这些成分是如何运输到轴突中的。该项目的起点是一个新发现的突变，即完美连接(IMac)，在这种突变中，生长锥体似乎正确地导航到它们的目标位置，但突触并未形成。突触形成的过程受阻。该基因编码一种运动蛋白马达。该提议假设，这种马达是运输突触发生所需的物质所必需的，它不同于神经突起生长和导航所需的一个或多个马达。这项建议的目的是：1)表征突变体中轴突-靶点的相互作用，以确定需要iMac的程度；2)确定其运输依赖于iMac的特定突触分子，并研究iMac与这些物质耦合的方式；3)将其他Kinesin的功能与iMac的功能联系起来。通过这些实验，我们希望推进我们的长期目标，即阐明突触形成的机制。

DESCRIPTION (provided by applicant): For the assembly of a new synapse, the growing axon requires molecules for stabilizing early contacts, transforming the morphology of the axon, and building a functional connection between the two cells. These molecules are synthesized in the cell body and must be transported down the axon. Indeed, the transport of synaptic building blocks is crucial to synaptogenesis and is likely to be closely regulated. It is also likely to be crucial to modifying synapses in the adult brain. So that we may ultimately understand the specificity and regulation of the motors in synaptogenesis, we propose to use Drosophila genetics to examine how those components are transported into the axon. The starting point of the project is a newly discovered mutation, immaculate connections (Imac) in which growth cones appear to navigate correctly to their targets, but synapses do not form. The process of synaptogenesis is blocked. This gene encodes a kinesin motor. The proposal hypothesizes that this motor is required for the transport of materials for synaptogenesis and that it is distinct from the motor or motors that are required for neurite outgrowth and navigation. The aims of this proposal are: 1) to characterize the axon-target interactions in the mutant to determine the extent to which Imac is required; 2) to determine specific synaptic molecules whose transport is dependent on Imac and to investigate the manner in which Imac couples to those cargos; 3) to relate the function of other kinesins to that of Imac. From these experiments, we hope to advance our long term goal of elucidating the mechanism by which synapses form.