Determining the Role of Dendrite Inhibition in Oligodendrocyte Myelination

确定树突抑制在少突胶质细胞髓鞘形成中的作用

• 批准号: 8596663
• 负责人: Stephanie Redmond
• 金额: $ 3.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596663
• 关键词: Action Potentials; Axon; Binding; Caliber; Coculture Techniques; Collaborations; Cues; Data; Demyelinating Diseases; Dendrites; Deposition; Development; Disease; Electron Microscopy; Excision; Fiber; Glycoproteins; Immunohistochemistry; In Vitro; Injury; Kinetics; Light; Membrane; Messenger RNA; Methods; Molecular; Motor Neurons; Mus; Myelin; Neuraxis; Neurons; Neurophysiology - biologic function; Oligodendroglia; Polystyrenes; Process; Proteins; Reading; Reporter; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Sorting - Cell Movement; Spinal Cord; Spinal Ganglia; System; Technology; Testing; Time; Transmembrane Domain; axon guidance; axon regeneration; cell fixing; cell type; deep sequencing; gray matter; improved; in vivo; insight; knock-down; myelination; nanofiber; new therapeutic target; novel; overexpression; paraform; precursor cell; prevent; public health relevance; receptor; remyelination; repaired; sample fixation; small hairpin RNA; therapeutic development; white matter

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.

描述（由申请人提供）：在正确的时间正确轴突的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）轴突都是无髓鞘的，直到少突胶质细胞（OL）从其前体细胞（OPC）分化出来，并开始在大多数轴突周围存款同心包裹绝缘膜，以促进动作电位的跳跃传导。很少有人知道OL轴突选择的分子调节剂，但只有合适的轴突的髓鞘形成可以通过（1）吸引阳性轴突线索，（2）排斥不合适的纤维，或诱导和抑制的组合来完成。出乎意料的是，我们的初步数据提出了第三种可能性，即OLs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仅选择阈值直径以上的纤维来髓鞘化。有趣的是，树突在几何形状上与轴突相似，但从未有髓鞘。因此我们 假设树突以接触依赖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，以（1）确定树突是否抑制OL髓鞘形成，以及（2）确定分子信号定位于树突膜，调节OL髓鞘形成。这是至关重要的，以确定少突胶质细胞如何相互作用，并避免树突了解正常的髓鞘动力学和深入了解脱髓鞘疾病。