Determining the Role of Dendrite Inhibition in Oligodendrocyte Myelination

描述（由申请人提供）：正确时间轴突的髓鞘形成对整个神经功能至关重要。在发育过程中，所有中枢神经系统（CNS）轴突都是无髓鞘的，直到少突胶质细胞（OLs）与其前体细胞（OPCs）分化，并开始在大多数轴突周围沉积同心绝缘膜，以促进动作电位的跳跃式传导。已知的OL轴突选择的分子调节因子很少，但只有适当轴突的髓鞘形成可能通过(1)吸引积极轴突信号，(2)排斥不适当的纤维，或诱导和抑制的结合来完成。出乎意料的是，我们的初步数据显示了第三种可能性；在髓鞘形成过程中，OLs感知并利用轴突直径，而不依赖于分子信号传导。OLs与轴突大小的聚苯乙烯纳米纤维共培养，只选择超过阈值直径的纤维形成髓鞘。有趣的是，树突在几何上与轴突相似，但从未有髓鞘。因此,我们

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.