Determining the Role of Dendrite Inhibition in Oligodendrocyte Myelination

描述(由申请人提供)：在正确的时间正确的轴突髓鞘形成对整体神经功能至关重要。在发育过程中，所有的中枢神经系统(CNS)轴突都是无髓的，直到少突胶质细胞(OL)从它们的前体细胞(OPC)分化出来，并开始在大多数轴突周围沉积同心的绝缘膜，以促进动作电位的跳跃传导。很少有人知道OL轴突选择的分子调控因素，但只有适当的轴突的髓鞘形成可能是通过(1)吸引积极的轴突线索，(2)不适当的纤维排斥，或诱导和抑制的组合来完成的。出乎意料的是，我们的初步数据提出了第三种可能性：OL在髓鞘形成中感知和使用轴突直径，而不依赖于分子信号。与轴突大小的聚苯乙烯纳米纤维共培养的OL只选择超过阈值直径的纤维进行髓鞘形成。有趣的是，树突在几何上类似于轴突，但从来没有髓鞘。因此，我们 假设树突以接触依赖的方式抑制少突胶质细胞的髓鞘形成。为了验证我们的假设，我将使用一种新的还原共培养系统来(1)确定树突是否抑制OL的髓鞘形成，以及(2)识别定位于树突膜的调节OL髓鞘形成的分子信号。确定少突胶质细胞如何与之相互作用，并避免树突，对于了解正常的髓鞘形成动力学和了解脱髓鞘疾病是至关重要的。

DESCRIPTION (provided by applicant): Myelination of correct axons at the right time is critical for overall neural function. During development, all central nervous system (CNS) axons are unmyelinated until oligodendrocytes (OLs) differentiate from their precursor cells (OPCs) and begin to deposit concentric wraps of insulating membrane around most axons to facilitate saltatory conduction of action potentials. Few molecular regulators of OL axon selection are known, but myelination of only appropriate axons may be accomplished by (1) attraction to positive axonal cues, (2) repulsion from inappropriate fibers, or a combination of induction and inhibition. Unexpectedly, our preliminary data suggest a third possibility; that OLs sense and use axon diameter in myelination independent of molecular signaling. OLs cocultured with axon-sized polystyrene nanofibers select only fibers above a threshold diameter to myelinate. Interestingly, the dendrite is geometrically similar to the axon, yet is never myelinated. Thus, we hypothesize that dendrites inhibit their myelination by oligodendrocytes in a contact- dependent manner. To test our hypothesis I will use a novel reductionist coculture system to (1) determine whether dendrites inhibit OL myelination, as well as (2) identify molecular signals localized to dendrite membranes that modulate OL myelination. It is critical to determine how oligodendrocytes interact with, and avoid dendrites to understand normal myelination kinetics and gain insight into dismyelinating diseases.