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: 7506647
• 负责人: Jonah R Chan
• 金额: $ 35.17万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7506647
• 关键词: Actins; Adaptor Signaling Protein; Address; Affect; Attenuated; Axon; Binding; Brain-Derived Neurotrophic Factor; C-terminal; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cell Polarity; Cell Survival; Cell division; Cell physiology; Cells; Communication; Complex; Cytoskeleton; Decision Making; Demyelinating Diseases; Dependence; Development; Disruption; Event; Family; Generations; Germ Cells; Growth Factor Receptors; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Individual; Lead; Localized; Membrane; Molecular; Multiple Sclerosis; Myelin; N-Cadherin; N-terminal; NGFR Protein; Nervous system structure; Neuregulin Receptor; Neuregulins; Neuroglia; Neurons; Numbers; Peripheral Nerves; Peripheral Nervous System Diseases; Play; Process; Proliferating; Proteins; Public Health; Recruitment Activity; Role; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Site; System; cell motility; migration; myelination; nerve injury; novel; polarized cell; receptor; research study; response; rho; scaffold; small hairpin RNA; transcription factor; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The generation of cell polarity is crucial for various cellular processes including cell migration, asymmetric division, and neuronal 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 remains 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 axon-glial junction, and disruption of Par localization, dramatically inhibits myelination without affecting cell division, migration, or even axonal alignment. We demonstrate that various growth factor receptors and cellular adhesion molecules directly associate with the polarity complex and propose that the Par complex recruits these molecules to the axon-glial junction, polarizing the cell in order to initiate myelination. Our recent findings provide us with a rare opportunity to characterize the presence of this polarized molecular scaffold at the axon-glial junction 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. PUBLIC HEALTH RELEVANCE Neurons and glia share a mutual dependence in establishing a functional relationship that is controlled by the integration of complex molecular signals and pathways. These reciprocal interactions are responsible for multiple processes, including cell survival, proliferation, migration, cell-fate determination, and differentiation. The formation of myelin is an exquisite and dynamic example of cell-cell interaction that involves the myelin- forming cell and the neuron. 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 after nerve injury.

描述（由申请人提供）：细胞极性的产生对各种细胞过程至关重要，包括细胞迁移，不对称分裂和神经元规范。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起着至关重要的作用，从而帮助细胞做出有关命运、取向、分化和相互作用的决定。在神经系统中，神经元和神经胶质相互依赖，建立功能关系，其中最明显的是神经胶质在轴突周围形成髓磷脂的过程。髓磷脂的形成是细胞-细胞相互作用的一个精细例子，它包括在轴突-神经胶质界面处开始的轴突周围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，但在其形成过程中细胞极性的参与在很大程度上仍然是未知的。我们最近发现了Par（分配缺陷）极性复合物在髓鞘形成过程中的新作用。这种极性复合物不对称地定位于轴突-胶质交界处的髓鞘形成细胞中，Par定位的破坏可显著抑制髓鞘形成，而不影响细胞分裂、迁移甚至轴突排列。我们证明了各种生长因子受体和细胞粘附分子与极性复合物直接相关，并提出Par复合物将这些分子招募到轴突-胶质连接处，使细胞极化以启动髓鞘形成。我们最近的发现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轴突-胶质连接处导致髓鞘形成单向激活的存在。清楚地了解髓磷脂形成细胞的分子和细胞事件，对于推进脱髓鞘疾病（如多发性硬化症、周围神经病变，甚至神经损伤）的治疗至关重要。神经元和神经胶质在建立由复杂分子信号和通路整合控制的功能关系方面具有相互依赖性。这些相互作用负责多种过程，包括细胞存活、增殖、迁移、细胞命运决定和分化。髓磷脂的形成是细胞-细胞相互作用的一个微妙而动态的例子，它涉及髓磷脂形成细胞和神经元。清楚地了解髓磷脂形成细胞的分子和细胞事件，对于推进脱髓鞘疾病（如多发性硬化症、周围神经病变，甚至神经损伤后）的治疗至关重要。