Mechanisms in CNS Myelination: Role of PD-Ialpha/ATX

项目总结 在中枢神经系统(CNS)的发育过程中，少突胶质前体细胞在 分离的生发区，它们从那里迁移到预期的有髓区域。在这些最终目的地， 少突胶质细胞成为髓鞘前、迁移后的细胞，延伸一个巨大而复杂的过程 寻找有髓鞘的轴突节段的网络。在适当的靶相互作用后，预髓鞘形成， 迁移后的少突胶质细胞过程从突起向膜片形成过渡。 少突胶质细胞成熟的这些关键的最终和不同的步骤受到以下复杂的相互作用的调节 少突胶质细胞S突起，即突起，及其细胞外环境，它们被考虑 对高效的髓鞘形成至关重要。然而，对细胞外因子和分子却知之甚少。 协调复杂的事件序列的机制，这些事件发生在 突起延伸到一个复杂的突起网络，然后延伸到髓鞘细胞。因此，作为一个 更好地理解髓鞘形成的调节，这些的长期目标 研究是为了洞察伸展的突起的生长和成熟的调节 髓鞘形成前、迁移后的少突胶质细胞。我们实验室产生的数据表明 基质细胞蛋白磷酸二酯酶-Ia/自体趋化蛋白(PD-Ia/ATX)，由髓鞘形成前、迁移后释放 少突胶质细胞在髓鞘形成的初期，对成熟期起着至关重要的作用。 少突胶质细胞突起。根据我们公布的和初步的数据，我们制定了中央 PD-Ia/ATX促进早期髓鞘前期、迁移后进展的假说 通过三种细胞的协同作用，将少突胶质细胞转化为具有全功能的髓鞘细胞 截然不同的功能活跃的站点。特别是，我们计划完成以下研究，以解决 上述中心假设：1)我们将在体外表征以下分子机制： 由PD-Ia/ATx？S Morfo结构域的两个功能活性中心介导并参与其中 在促进髓鞘成熟的过程中，迁移后的少突胶质细胞突入复合体 过程网络。2)我们将在体外研究PD-Ia/ATX介导的分子机制。S 溶血磷脂酶D活性部位和参与促进髓鞘前成熟、迁移后 少突胶质细胞突入膜片。3)我们将在体内表征PD-Ia/ATX和 其在少突胶质细胞突起重塑和初始髓鞘形成中的功能活性部位 将斑马鱼作为一个模型系统。在这些和随后的调查中获得的数据可能会 不仅大大提高了我们对发育中髓鞘形成的了解，而且它们还可能解开 改善髓鞘再生的新治疗靶点。

PROJECT SUMMARY During development of the central nervous system (CNS), oligodendrocyte progenitor cells are generated in discrete germinal zones from where they migrate to prospective myelinated areas. At these final destinations, oligodendrocytes become premyelinating, post-migratory cells that extend a large and complex process network in search for axonal segments to be myelinated. Upon appropriate target interaction, premyelinating, post-migratory oligodendrocyte processes transition from process outgrowth to membrane sheet formation. These critical final and distinct steps of oligodendrocyte maturation are regulated by complex interactions of the oligodendrocyte¿s protrusions, i.e. processes, with their extracellular environment, and they are considered crucial for efficient myelination. However, little is known about the extracellular factors and molecular mechanisms coordinating the intricate sequence of events that occurs during the progression from a few process bearing to a complex process network extending and then to a myelinating cell. Thus, as an approach toward a better understanding of the regulation of myelination, the long-term goal of these studies is to gain insight into the regulation of outgrowth and maturation of protrusions extended by premyelinating, post-migratory oligodendrocytes. Data generated in our laboratory suggest that the matricellular protein phosphodiesterase-Ia/autotaxin (PD-Ia/ATX), which is released by premyelinating, postmigratory oligodendrocytes during the initial stages of myelination, plays a crucial role for the maturation of oligodendrocyte protrusions. Based on our published and preliminary data we formulate the central hypothesis that PD-Ia/ATX promotes the progression from an early stage premyelinating, postmigratory oligodendrocyte into a fully functional, i.e. myelinating cell, via the concerted action of three distinct functionally active sites. In particular, we are planning to complete the following studies to address the above stated central hypothesis: 1) We will characterize in vitro the molecular mechanisms that are mediated by the proposed two functionally active sites of PD-Ia/ATX¿s MORFO domain and that are involved in promoting the maturation of premyelinating, post-migratory oligodendrocyte protrusions into a complex process network. 2) We will characterize in vitro the molecular mechanisms that are mediated by PD-Ia/ATX¿s lysoPLD active site and that are involved in promoting the maturation of premyelinating, post-migratory oligodendrocyte protrusions into membrane sheets. 3) We will characterize in vivo the role of PD-Ia/ATX and its functionally active sites on the remodeling of oligodendrocyte protrusions and on initial myelination using the zebrafish as a model system. The data obtained in these and subsequent investigations are likely to significantly advance not only our knowledge about developmental myelination but they may also unravel novel therapeutic targets for improving remyelination.