The establishment of Schwann cell polarity and the initiation of myelination

雪旺细胞极性的建立和髓鞘形成的启动

• 批准号: 8762139
• 负责人: Jonah R Chan
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762139
• 关键词: Actins; Action Potentials; Adaptor Signaling Protein; Address; Adult; Affect; Alanine; Apical; Attenuated; Axon; Brain-Derived Neurotrophic Factor; Cell Communication; Cell Maturation; Cell Polarity; Cell division; Cell membrane; Cell physiology; Cells; Cellular Morphology; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; DNA Sequence Rearrangement; Data; Decision Making; Demyelinating Diseases; Demyelinations; Dependence; Development; Disease; Dominant-Negative Mutation; Equilibrium; Event; Family; Gene Expression; Generations; Guanine Nucleotide Exchange Factors; Injury; Knockout Mice; Knowledge; Lead; Link; Mediating; Membrane; Molecular; Monomeric GTP-Binding Proteins; Multiple Sclerosis; Mutation; Myelin; NGFR Protein; Nervous system structure; Neuroglia; Neurons; PAWR gene; Pathway interactions; Peripheral Nervous System Diseases; Phosphorylation; Play; Process; Proteins; Recruitment Activity; Regulation; Relative (related person); Role; STK11 gene; Schwann Cells; Series; Serine; Signal Transduction; Site; Sorting - Cell Movement; Tumor Suppressor Proteins; base; loss of function; migration; mutant; myelination; nerve injury; novel; protein function; public health relevance; receptor; research study; rho; scaffold; sciatic nerve; spatiotemporal; transmission process

DESCRIPTION (provided by applicant): Cell polarity is critical for various cellular processes including establishing the antero-posterior axis, generating distinct membrane specializations (apical and basal polarity), as well as asymmetric cell division and axon specification. Essentially, cell polarity plays fundamental roles in helping to organize and integrate complex molecular signals in order for cells to make decisions concerning fate, orientation, differentiation, and interaction. In the nervous system, neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which glia form myelin around axons. The formation of myelin is an exquisite example of cell-cell interaction, which consists of the polarized or unidirectional wrapping of multiple layers of membrane concentrically around an axon initiated at the site of the axon-glial interface. While myelination is a highly polarized process, the involvement of cell polarity in its formation remain largely uncharacterized. We have recently identified a novel role for the Par (partitioning defective) polarity complex in the initiation of myelination. This polarity complex localizes asymmetrically in myelin- forming cells at the SC-axon interface, and disruption of Par localization, dramatically inhibits myelination without affecting cell division, migration, or even axonal alignment. The central hypothesis of this proposal is that axonal signals facilitate the "breaking of symmetry" in the SC and initiate myelination by coordinating cytoskeletal dynamics/rearrangement and gene expression. Our recent findings provide us with a rare opportunity to characterize the presence of this polarized molecular scaffold at the SC-axon interface that leads to the unidirectional activation of myelination. A clear understanding of the molecular and cellular events that pave the way for the myelin-forming cell is vital in advancing therapies for demyelinating diseases such as Multiple Sclerosis, the peripheral neuropathies, and even nerve injury.

描述（由申请人提供）：细胞极性对于各种细胞过程至关重要，包括建立前后轴、产生不同的膜特化（顶端和基底极性）以及不对称细胞分裂和轴突特化。从本质上讲，细胞极性在帮助组织和整合复杂的分子信号方面发挥着重要作用，以便细胞做出有关命运，方向，分化和相互作用的决定。在神经系统中，神经元和神经胶质在建立功能关系方面具有相互依赖性，其中最明显的莫过于神经胶质在轴突周围形成髓鞘的过程。髓磷脂的形成是细胞-细胞相互作用的一个极好的例子，其包括在轴突-神经胶质界面的位点处起始的围绕轴突同心的多层膜的极化或单向包裹。虽然髓鞘形成是一个高度极化的过程，但其形成中细胞极性的参与在很大程度上仍然没有特征。我们最近发现了一个新的作用Par（分区缺陷）极性复杂的髓鞘形成的启动。这种极性复合物不对称地定位在SC-轴突界面处的髓鞘形成细胞中，并且Par定位的破坏显著地抑制髓鞘形成，而不影响细胞分裂、迁移，甚至是神经细胞的分化。 轴突排列该建议的中心假设是轴突信号促进SC中的“对称性破坏”，并通过协调细胞骨架动力学/重排和基因表达来启动髓鞘形成。我们最近的研究结果为我们提供了一个难得的机会来表征这种极化分子支架在SC-轴突界面的存在，导致髓鞘形成的单向激活。清楚地了解为髓鞘形成细胞铺平道路的分子和细胞事件对于推进脱髓鞘疾病（如多发性硬化症、周围神经病甚至神经损伤）的治疗至关重要。