THE ESTABLISHMENT OF SCHWANN CELL POLARITY AND THE INITIATION OF MYELINATION

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指定。从本质上讲，细胞极性在帮助组织和整合复杂的分子信号以便细胞做出关于命运、方向、分化和相互作用的决定方面起着基础性的作用。在神经系统中，神经元和神经胶质细胞在建立功能关系方面相互依赖，其中最明显的是神经胶质细胞在轴突周围形成髓鞘的过程。髓鞘的形成是细胞-细胞相互作用的一个很好的例子，它包括在轴突-神经胶质界面开始的位置围绕轴突同心地包裹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，但细胞极性在其形成过程中的参与在很大程度上仍不清楚。我们最近发现了PAR(分割缺陷)极性复合体在髓鞘形成的启动中的一个新的作用。这种极性复合体不对称地定位于轴突-神经胶质交界处的髓鞘形成细胞中，PAR定位的中断显著抑制了髓鞘的形成，而不影响细胞的分裂、迁移，甚至轴突的排列。我们证明了各种生长因子受体和细胞黏附分子直接与极性复合体相关，并提出PAR复合体将这些分子招募到轴突-神经胶质连接，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描述这种极化的分子支架在轴突-神经胶质交界处的存在，它导致了髓鞘的单向激活。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多发性硬化症、周围神经病甚至神经损伤等脱髓鞘疾病的治疗至关重要。与公共健康相关的神经元和神经胶质细胞在建立受复杂分子信号和通路整合控制的功能关系方面相互依赖。这些相互作用负责多个过程，包括细胞生存、增殖、迁移、决定细胞命运和分化。髓鞘的形成是一个涉及髓鞘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多发性硬化症、周围神经病甚至神经损伤后脱髓鞘疾病的治疗至关重要。

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.