Guidance of Oligodendrocyte Processes: The Role of Local Protein Synthesis

提供了 在中枢神经系统（CMS）的发育过程中，神经元和神经元的迁移后细胞（post-migration cells）都发生了变化。 少突神经胶质细胞发出的过程，导航通过实质寻找一个目标 诱导它们成熟信号，即神经元的突触形成和 少突胶质细胞这种过程导航的调节已经在神经元中得到很好的表征。 细胞，其中感觉运动结构，神经元生长锥，位于过程尖端是“细胞器” 它能感知环境信号相比之下，令人惊讶的是， 寻路和瞄准我们的初步数据表明，少突胶质细胞的过程中， 它们的远端是在结构和功能上类似于神经生长锥的“细胞器”， 将其称为少突胶质细胞生长锥样结构（OLG-生长锥）。在神经元中，mRNA 生长锥内的运输和局部限制的蛋白质合成被认为是 轴突/神经突寻路和靶向。我们的初步数据表明， 可能对少突胶质细胞过程的寻路和靶向是重要的。因此，我们制定了 中心假设，髓鞘形成前，迁移后少突胶质细胞具有OLG生长 含有mRNA的视锥细胞，其局部限制性翻译对于调节 少突胶质细胞过程寻路和靶向，即髓鞘形成。这一假设将在 两个具体目标。1)我们将确定OLG生长锥中局部限制性蛋白质合成的作用， 寻路，特别是用于响应于非许可线索的向化转向。的此集合中 实验在何种程度上局部限制蛋白质合成发生在寻路OLG生长锥 将被确定。此外，分离过程的趋化性转向将在抑制后进行分析 蛋白质的合成。预期局部限制性蛋白质合成的抑制将干扰OLG-1。 生长锥向化性转向反应。2)使用微阵列的方法，我们将确定mRNA， 存在于OLG生长锥中，特异性地响应轴突靶向信号。这套 预计实验将揭示对OLG生长锥靶向重要的候选蛋白质，即 髓鞘形成的起始。在继续根据本提案的调查结果进行研究时， 我们正计划进一步鉴定这些蛋白质。因此，拟议的研究代表了第一步 一组旨在更好地了解少突胶质细胞寻路过程的调节的实验 和目标。这种知识的进步特别令人感兴趣，因为过程中的缺陷 生长和轴突识别似乎是修复存在于神经纤维瘤中的病变的主要限制因素之一。 患有人类主要脱髓鞘疾病多发性硬化症的患者的CMS。

PROVIDED. During development of the central nervous system (CMS) post-migratory cells of both neuronal and oligodendroglial origin send out processes that navigate through the parenchyma in search for a target signal that induces their maturation, i.e synapse formation for neuronal and myelin sheath formation for oligodendroglial cells. The regulation of this process navigation has been well characterized for neuronal cells, where a sensorimotor structure, the neuronal growth cone, located at the process tip is the "organelle" that senses environmental cues. In contrast, surprisingly little is known about oligodendroglial process pathfinding and targeting. Our preliminary data demonstrate that oligodendrocyte processes possess at their distal ends "organelles" that structurally and functionally resemble neuronal growth cones and that we will refer to as oligodendroglial growth cone-like structures (OLG-growth cones). In neurons, mRNA transport and locally restricted protein synthesis within the growth cone are considered main regulators of axon/neurite pathfinding and targeting. Our preliminary data suggest that similar regulatory mechanisms may be important for the pathfinding and targeting of oligodendrocyte processes. Thus, we formulate the central hypothesis that premyelinating, post-migratory oligodendrocytes possess OLG-growth cones that containmRNAs, the locally restricted translation of which is critical for the regulation of oligodendroglial process pathfinding and targeting, i.e. myelination. This hypothesis will be tested in two specific aims. 1) We will determine the role of locally restricted protein synthesis for OLG-growth cone pathfinding and in particular for chemotropic turning in response to non-permissive cues. In this set of experiments the extent to which locally restricted protein synthesis occurs in pathfinding OLG-growth cones will be determined. In addition, chemotropic turning of separated processes will be analyzed after inhibition of protein synthesis. It is expected that inhibition of locally restricted protein synthesis will perturb OLG- growth cone chemotropic turning responses. 2) Using a microarray approach, we will identify mRNAs that are present in OLG-growth cones specifically in response to axonal targeting signals. This set of experiments is expected to reveal candidate proteins that are important for OLG-growth cone targeting, i.e. the initiation of myelin sheath formation. In continuing studies based on the findings of the present proposal, we are planning to further characterize these proteins. The proposed studies thus represent a first step into a set of experiments designed to better understand the regulation of oligodendrocyte process pathfinding and targeting. Such advancement in knowledge is of particular interest since deficiencies in process outgrowth and axon recognition appear to be among the main limiting factors for repair of lesions present in the CMS of patients suffering from the major demyelinating disease in humans, Multiple Sclerosis.