The establishment of Schwann cell polarity and the initiation of myelination

描述（由申请人提供）：细胞极性对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（尖极性和基极性），以及不对称的细胞分裂和轴突规范。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未被表征。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。这种极性复合物在sc -轴突界面的髓磷脂形成细胞中不对称地定位，并且Par定位的破坏显着抑制髓鞘形成，而不影响细胞分裂，迁移或甚至

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.