Molecular Basis of Oligodendrocyte Development

描述（由申请人提供）：脊髓内少突胶质细胞的发育和髓鞘节间的产生取决于来自脊索和底板的区域信号以及神经元或轴突来源的信号。脊索和底板衍生的信号，特别是超音hedgehog基因，对于谱系的具体描述是必要的，而轴突信号在少突胶质细胞发育的早期和晚期似乎都很重要。神经调节蛋白-1是正常脊髓少突胶质细胞发育所必需的分子之一，它定位于底板以及大多数神经元及其轴突中。在缺乏神经调节蛋白-1的情况下，O4+前突胶质细胞不能在脊髓外植体中发育。在神经调节蛋白-1功能缺失突变体中加入重组神经调节蛋白-1可以恢复前毛突成胶质细胞的发育。少突胶质细胞通过激活作为信号转导异二聚体的erbB受体酪氨酸激酶家族成员来响应神经调节因子。我们最近发现erbB2受体酪氨酸激酶在少突胶质细胞前体发育的早期阶段不是必需的，但对于前突胶质细胞分化为半乳糖脑苷阳性（GalC+）少突胶质细胞（终末分化）是必不可少的。在erbB2的存在下，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，Ga1C+少突胶质细胞的数量减少10倍以上，少突胶质细胞的发育在前毛突成胶质细胞阶段停止。少数erbB2-/-少突胶质细胞确实分化到成熟，但它们不能通过形成髓鞘节间与神经突相互作用。这些数据表明erbB2是少突胶质细胞终末分化和髓鞘形成所必需的。我们的数据和其他实验室的数据共同支持神经调节蛋白及其受体在少突胶质细胞发育的多个阶段的整体作用。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（包括髓鞘形成）的早期、终末分化之前和晚期都是必要的。特异性目的1侧重于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。这一目标将需要对神经调节蛋白1、erbB3和erbB4突变小鼠脊髓中的grp、OPCs和前突胶质母细胞进行完整的分析。特异性目的2将确定神经调节蛋白信号在早期少突胶质细胞发育中的存活和分化。特异性Aim 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。特异性Aim 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.