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：
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
项目类别：
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

项目摘要

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，产生独特的膜专业（顶端和基础极性），以及不对称的细胞分裂和轴突规范。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。尽管髓鞘化是一个高度极化的过程，但细胞极性参与其形成的过程仍然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SC-AXON界面处不对称地定位于髓鞘形成细胞，并破坏PAR定位，极大地抑制髓鞘形成，而不会影响细胞分裂，迁移甚至什至轴突对准。该提议的中心假设是轴突信号促进了SC中的“对称性”，并通过协调细胞骨架动力学/重排和基因表达来启动髓鞘。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SC-axon界面上的存在，从而导致髓鞘形成的单向激活。对为髓磷脂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（例如多发性硬化症，周围神经病甚至神经损伤）至关重要。