Supplement: Regulation of Axonal Transport At Branch Junctions

项目摘要 轴突运输对神经系统的发育和功能至关重要。轴突运输 依赖于马达蛋白（驱动蛋白和动力蛋白）沿沿着移动蛋白质、膜和RNA货物。 这对长的、通常高度分支的轴突尤其重要，因为这些轴突需要细胞中制造的构建模块 体或轴突末梢接收的信号进行长距离运输。最近的研究表明， 确定了许多调节机制，包括马达蛋白与晶格结合蛋白之间的相互作用， 微管相关蛋白（MAPs），在不同的轴突区域。然而，轴突运输是如何 如何控制货物进出分行的问题还没有得到很好的理解。这是一个突出的问题， 轴突分支存在于整个神经系统中。它们不仅定义了神经元的形状， 控制突触连接和特异性，影响结构可塑性，促进功能再生 伤后建议的研究将以我们对以下方面的长远兴趣为基础， 分支的形态发生和细胞骨架的调节以及最近在分支中发现的MAP 发展和交通管理。我们的初步数据表明，在分支连接处的运输是高度 选择性，因为货物优先运输到生长的树枝。此外，我们还发现MAP7， 一种定位于分支连接处并与正端运动驱动蛋白1相互作用的MAP，影响转运 行为和分支生长。因此，我们假设在分支连接处的轴突运输是由一个 选择性路由机制，由特定的电机MAP相互作用介导。为了验证这个假设，我们 将：1）建立选择性运输和分支生长之间的功能联系; 2）剖析机制 由MAP7介导;和3）建立选择性路由作为轴突运输中的共同特征。通过专注 在轴突的一个重要区域，过去没有被研究过，这些研究不仅会填补空白， 在我们对轴突运输的理解中，也为突触的发育和功能提供了新的见解。 鉴于轴突运输在许多神经和神经退行性疾病中的重要性， MAP7和驱动蛋白-1与癫痫和ALS的关联，我们提出的基础神经元细胞的研究 生物学问题将为揭示疾病机制提供新的知识，因此与 NIH的使命是了解和增进人类健康。

PROJECT ABSTRACT Axonal transport is essential to development and function of the nervous system. Axonal transport relies on motor proteins (kinesins and dynein) to move protein, membrane and RNA cargos along microtubules. It is especially important to long and often highly branched axons that requires building blocks made in the cell body or signals received at axonal terminals to be transported for long distance. Recently studies have identified many regulatory mechanisms, including the interactions between motor proteins with lattice-bound microtubule associated proteins (MAPs), in different axonal regions. However, how axonal transport is regulated to steer cargos into and out of branches is not well understood. This is an outstanding problem as axonal branches are present throughout the nervous system. They not only define neuronal shape, but also control synaptic connectivity and specificity, influence structural plasticity, and promote functional regeneration after injury. The proposed study will tackle this under-studied problem by building on our long-term interest in branch morphogenesis and cytoskeleton regulation as well as a recent discovery of a MAP in branch development and transport regulation. Our preliminary data showed that transport at branch junctions is highly selective as cargos are preferentially transported into growing branches. In addition, we also found that MAP7, a MAP that is localized to branch junctions and interacts with the plus end motor kinesin-1, influences transport behavior and branch growth. We thus hypothesize that axonal transport at branch junctions is controlled by a selective routing mechanism that is mediated by specific motor-MAP interactions. To test this hypothesis, we will: 1) establish a functional link between selective transport and branch growth; 2) dissect the mechanism mediated by MAP7; and 3) establish selective routing as a common feature in axonal transport. By focusing on an important region of the axon that has not been studied in the past, these studies will not only fill in a gap in our understanding of axonal transport, but also provide new insights into synaptic development and function. Given the importance of axonal transport in many neurological and neurodegenerative disorders, and the association of MAP7 and kinesin-1 with epilepsy and ALS, our proposed studies of a basic neuronal cell biological problem will provide new knowledge to uncover disease mechanisms, and thus are highly relevant to the NIH mission to understand and enhance human health.