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

基本信息

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
项目类别：
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

项目摘要

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包括细胞迁移，不对称分裂和神经元规范在内的各种细胞过程至关重要。本质上，细胞极性在有助于组织和整合复杂的分子信号方面起着基本作用，以便细胞做出有关命运，方向，分化和相互作用的决策。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，并且没有比胶质在轴突周围形成髓磷脂的过程更明显。髓磷脂的形成是细胞 - 细胞相互作用的精美例子，由在轴突 - 镀膜界面的位置引发的轴突周围围绕轴突进行偏振或单向包裹。虽然髓鞘化是一个高度极化的过程，但细胞极性在其形成中的参与在很大程度上没有表征。我们最近确定了在髓鞘启动中的PAR（分配缺陷）极性复合物的新作用。这种极性复合物在轴突 - 胶质结处的髓磷脂形成细胞中不对称地定位，并破坏了PAR定位，极大地抑制髓鞘形成，而不会影响细胞分裂，迁移，甚至轴突比对。我们证明，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，并提出PAR复合物将这些分子募集到轴突 - 胶质结上，从而使细胞偏振以启动髓鞘形成。我们最近的发现为我们提供了一个难得的机会，可以表征这种极化分子支架在轴突胶质连接处的存在，从而导致髓鞘形成的单向激活。对髓鞘形成细胞铺平道路的分子和细胞事件的清晰理解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）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，该功能关系由复杂的分子信号和途径的整合控制。这些相互相互作用负责多种过程，包括细胞存活，增殖，迁移，命令测定和分化。髓磷脂的形成是涉及髓磷脂形成细胞和神经元的细胞间相互作用的精致和动态的例子。对为髓磷脂形成细胞铺平道路的分子和细胞事件的清晰了解对于推进脱髓鞘疾病（例如多发性硬化症，周围神经病）以及神经损伤后的疗法至关重要。