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: 8136007
• 负责人: Jonah R Chan
• 金额: $ 32.67万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136007
• 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; Event; Family; Generations; Germ Cells; Growth Factor Receptors; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Individual; Lead; Membrane; Molecular; Multiple Sclerosis; Myelin; N-Cadherin; N-terminal; NGFR Protein; Nervous system structure; Neuregulin Receptor; Neuregulins; Neuroglia; Neurons; Peripheral Nerves; Peripheral Nervous System Diseases; Play; Process; Proliferating; Proteins; Recruitment Activity; Role; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Site; System; adhesion receptor; 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）：细胞极性的产生对于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。这种极性复合物在轴突-神经胶质连接处的髓鞘形成细胞中不对称地定位，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、迁移或甚至轴突排列。我们证明了各种生长因子受体和细胞粘附分子直接与极性复合物相关联，并提出Par复合物将这些分子招募到轴突-神经胶质连接处，使细胞极化以启动髓鞘形成。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的分子支架在轴突-胶质细胞连接处的存在，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。公共卫生相关性神经元和神经胶质在建立功能关系方面具有相互依赖性，这种功能关系由复杂分子信号和途径的整合控制。这些相互作用负责多个过程，包括细胞存活、增殖、迁移、细胞命运决定和分化。髓磷脂的形成是涉及髓磷脂形成细胞和神经元的细胞-细胞相互作用的精致和动态的例子。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后）的治疗至关重要。