Molecular Basis of Oligodendrocyte Development

描述(申请人提供)：少突胶质细胞的发育和脊髓内髓鞘节间的产生依赖于来自脊索和底板的区域信号以及来自神经元或轴突的信号。脊索和底板来源的信号，特别是声波刺猬，似乎是确定谱系所必需的，而轴突信号在早期和晚期的少突胶质细胞发育中似乎都很重要。NeuRegin-1是正常脊髓少突胶质细胞发育所必需的分子之一，定位于脊髓底板以及大多数神经元及其轴突中。在没有神经调节蛋白-1的情况下，O4+前树突状细胞不会在脊髓外植体中发育。在神经调节蛋白-1功能丧失的突变体中，通过添加重组神经调节蛋白-1，可以恢复前树突状细胞的发育。少突胶质细胞对神经调节蛋白的反应是通过激活作为信号转导异源二聚体的erbB受体酪氨酸激酶家族成员来实现的。我们最近发现，在少突胶质细胞前体发育的早期阶段，erbB2受体酪氨酸激酶不是必需的，但对于前突胶质母细胞分化为半乳糖脑苷脂阳性(GalC+)少突胶质细胞(终末分化)是必不可少的。在erbB2存在的情况下，少突胶质细胞的发育和髓鞘形成是正常的。然而，在缺乏erbB2(erbB2-/-)的情况下，少突胶质细胞的发育在原树突细胞阶段停止，Ga1C+少突胶质细胞的数量减少了10倍以上。在少数进行分化至成熟的erbB2-/-少突胶质细胞中，这些细胞不能通过形成髓鞘节间与轴突相互作用。这些数据表明，在少突胶质细胞的终末分化和髓鞘形成过程中，erbB2是必需的。总而言之，我们的数据和来自其他实验室的数据支持了神经调节蛋白及其受体在少突胶质细胞发育的多个阶段发挥的不可或缺的作用。我们的总体假设是，神经调节蛋白介导的信号在少突胶质细胞发育的早期、终末分化之前和后期都是必要的，包括髓鞘形成。具体目的1主要研究神经调节蛋白介导的信号在早期少突胶质细胞发育中的作用。这一目标将需要对NeuRegin-1、erbB3和ERBB4突变小鼠脊髓中的GRPs、OPC和前树突状细胞进行完整的分析。具体目标2将确定在早期少突胶质细胞发育过程中，神经调节蛋白是否发出存活和分化的信号。具体目标3将确定erbB2、erbB3或ERBB4对少突胶质细胞发育的影响是否是细胞自主的。具体目标4将确定神经调节蛋白是否是少突胶质细胞终末分化和髓鞘形成的轴突信号。

DESCRIPTION (provided by applicant): Development of oligodendrocytes and the generation of myelin internodes within the spinal cord depends upon regional signals derived from the notochord and floor plate and upon neuronal or axonally derived signals. Notochord and floor plate derived signals, in particular sonic hedgehog, appear necessary for specification of the lineage whereas axonal signals appear to be important in both early and late oligodendrocyte development. Neuregulin-1, which is localized in the floor plate as well as in most neurons and their axons, is one of the molecules necessary for normal spinal cord oligodendrocyte development. In the absence of neuregulin-1, O4+ proligodendroblasts do not develop in spinal cord explants. Development of proligodendroblasts can be restored in neuregulin-1 loss-of-function mutants by addition of recombinant neuregulin-1. Oligodendrocytes respond to neuregulins by activating members of the erbB receptor tyrosine kinase family which function as signal transducing heterodimers. We have recently shown that the erbB2 receptor tyrosine kinase is not necessary for the early stages of oligodendrocyte precursor development but is essential for proligodendroblasts to differentiate into galactosylcerebroside positive (GalC+) oligodendrocytes (terminal differentiation). In the presence of erbB2, oligodendrocyte development and myelination are normal. However, in the absence of erbB2 (erbB2-/-) oligodendrocyte development is halted at the proligodendroblast stage with a greater than 10-fold reduction in the number of Ga1C+ oligodendrocytes. Of the minority of erbB2-/- oligodendrocytes that do proceed to differentiate to maturity, these fail to interact with neurites by forming myelin internodes. These data suggest that erbB2 is required for the terminal differentiation of oligodendrocytes and myelination. Together our data and that from other labs supports an integral role for neuregulins and their receptors at multiple stages of oligodendrocyte development. Our overall hypothesis is that neuregulin mediated signals are necessary both at early, prior to terminal differentiation, and late stages of oligodendrocyte development including myelination. Specific Aim 1 focuses on the function of neuregulin mediated signals in early oligodendrocyte development. This aim will entail a complete analysis of GRPs, OPCs and proligodendroblasts in mouse spinal cords from neuregulin-1, erbB3, and erbB4 mutant mice. Specific Aim 2 will determine if neuregulin signals survival versus differentiation in early oligodendrocyte development. Specific Aim 3 will determine if the effects of erbB2, erbB3 or erbB4 on oligodendrocyte development are cell autonomous. Specific Aim 4 will determine if neuregulin is an axonal signal for terminal differentiation of oligodendrocytes and myelination.