Regulation of Axonal Transport At Branch Junctions

轴突运输对于神经系统的发育和功能至关重要。轴突运输 依靠运动蛋白（驱动蛋白和动力蛋白）沿着微管移动蛋白质、膜和 RNA 货物。 这对于长且通常高度分支的轴突尤其重要，因为轴突需要在细胞中制造构建块 身体或轴突终端接收到的信号将被长距离传输。最近研究有 确定了许多调节机制，包括运动蛋白与晶格结合蛋白之间的相互作用 不同轴突区域的微管相关蛋白（MAP）。然而，轴突运输是如何进行的？ 对引导货物进出分支机构的监管尚不清楚。这是一个突出的问题 轴突分支遍布整个神经系统。它们不仅定义了神经元的形状，还定义了 控制突触连接性和特异性，影响结构可塑性，促进功能再生 受伤后。拟议的研究将通过建立我们对以下问题的长期兴趣来解决这个尚未充分研究的问题： 分支形态发生和细胞骨架调节以及最近发现的分支中的 MAP 发展和运输监管。我们的初步数据显示，支路路口的交通状况非常好。 选择性，因为货物优先运输到正在生长的分支机构。此外，我们还发现MAP7， 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，影响运输 行为和分支生长。因此，我们假设分支连接处的轴突运输是由 由特定运动-MAP 相互作用介导的选择性路由机制。为了检验这个假设，我们 将：1）在选择性运输和分支生长之间建立功能联系； 2）剖析机制 由 MAP7 介导； 3）建立选择性路由作为轴突运输的共同特征。通过聚焦 针对过去从未研究过的轴突重要区域，这些研究不仅将填补一项空白 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系统和神经退行性疾病中的重要性，以及 MAP7 和驱动蛋白-1 与癫痫和 ALS 的关联，我们提出的对基本神经元细胞的研究 生物学问题将为揭示疾病机制提供新知识，因此与疾病高度相关 NIH 的使命是了解和增强人类健康。

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.