髓鞘形成过程中神经元与少突胶质细胞间相互作用的分子机制研究

Oligodendrocytes are myelinating glial cells found in all regions of the central nervous system. The major function of oligodendrocytes is to form myelin sheaths around axons to ensure the rapid and faithful transmission of electrical signals. Myelination process is tightly regulated by intercellular signaling between axons and oligodendrocyte processes. Recently, it has been implicated that protein tyrosine phosphorylation mediated by surface receptor molecules plays important roles in this developmental process. However, the nature of ligands and receptors that are involved in axon-oligodendrocyte interactions during the myelination process has not been fully unraveled and characterized. To address this important issue, we carried out a large-scale in situ screening of receptor tyrosine kinases in early postnatal spinal cords and uncovered three receptor tyrosine kinases (Tyro3, DDR1 and EphB1) that are selectively up-regulated in myelinating oligodendrocytes in the developing CNS. Based on their temporal spatial pattern of expression and their molecular features related to cell adhesions, we hypothesize that these three receptor molecules participate in axon-oligodendrocyte binding and act in concert to regulate CNS myelination by activating the PI3K-Akt signaling pathway. This hypothesis will be tested by examining the effects of altering their expression and activity on myelin formation both in vitro and in vivo.

少突胶质细胞（OLs）是一群分布在中枢神经系统（CNS）所有区域中能形成髓鞘的神经胶质细胞。髓鞘形成过程是通过神经元轴突和OLs间的相互作用而逐步实现的。然而，参与髓鞘形成过程中神经元轴突与OLs相互作用的配体和受体的本质至今仍未被揭示和明确。近年来，调控蛋白酪氨酸磷酸化的细胞表面受体分子被认为在这一髓鞘发育过程中扮演着极为重要的角色。为解决这一重要问题，我们在出生后早期小鼠的脊髓组织中对受体酪氨酸激酶的表达进行了大规模的原位杂交筛选，结果发现在发育的CNS中有三个受体酪氨酸激酶（Tyro3、DDR1 和 EphB1）在形成髓鞘的OLs中特异性上调。基于它们的时空表达模式及其细胞粘着相关的分子特征，我们推测它们协同参与神经元轴突-OLs间相互作用。在此，我们将通过分子、细胞和遗传方法来检测它们在髓鞘形成过程中的作用。

在中枢神经系统（CNS）中少突胶质细胞是一种能缠绕轴突形成髓鞘的大胶质细胞。髓鞘的主要功能是提供一个绝缘环境使得电信号可以沿着轴突迅速准确的传递。紧密的髓鞘通过低电容高电阻阻止了神经传导中的离子交换。髓鞘形成过程受到轴突和少突胶质细胞间的胞间信号通路的严格调节。近年来，细胞表面受体分子调控蛋白质酪氨酸磷酸化被认为在这一发育过程中扮演着极为重要的角色。然而，参与髓鞘形成过程中与轴突-少突胶质细胞相互作用的配体和受体的本质还没有被完全地揭示和明确。. 我们的前期研究结果证明Tyro3，DDR1和ErbB1受体酪氨酸激酶在出生后小鼠脊髓的正在形成髓鞘的少突胶质细胞中选择性上调表达。所有这三个受体都含有参与细胞间互作或细胞与基质间互作的细胞外结构域。这三个酪氨酸激酶都有激活PI3-Akt激酶信号通路的能力。这些结果使我们得到这一假设：这三个受体的功能在于协同促进神经元-少突胶质细胞的互作及轴突的髓鞘化。我们将同时通过体内和体外实验检测改变他们的表达和活性对髓鞘形成过程的影响来证明这一假设。