Molecular Basis of Oligodendrocyte Development

少突胶质细胞发育的分子基础

基本信息

批准号：
6616692
负责人：
TIMOTHY VARTANIAN
金额：
$ 32.3万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2006-05-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：脊髓内少突胶质细胞的发育和髓磷脂节间的产生取决于源自脊索和底板的区域信号以及神经元或轴突衍生的信号。脊索和底板衍生的信号，特别是声波刺猬，似乎对于谱系的规范是必要的，而轴突信号似乎在早期和晚期少突胶质细胞发育中都很重要。 Neuregulin-1 位于底板以及大多数神经元及其轴突中，是正常脊髓少突胶质细胞发育所需的分子之一。在缺乏纽兰格林-1的情况下，O4+前胶质细胞在脊髓外植体中不会发育。通过添加重组神经调节蛋白-1，可以在神经调节蛋白-1 功能丧失突变体中恢复前突胶质细胞的发育。少突胶质细胞通过激活 erbB 受体酪氨酸激酶家族的成员来响应神经调节蛋白，该家族的成员充当信号转导异二聚体。我们最近表明，erbB2 受体酪氨酸激酶对于少突胶质细胞前体发育的早期阶段不是必需的，但对于原少突胶质细胞分化为半乳糖基脑苷脂阳性（GalC+）少突胶质细胞（终末分化）至关重要。在存在 erbB2 的情况下，少突胶质细胞发育和髓鞘形成正常。然而，在缺乏 erbB2 (erbB2-/-) 的情况下，少突胶质细胞发育在前幼突胶质细胞阶段停止，Ga1C+ 少突胶质细胞数量减少 10 倍以上。在少数确实继续分化成熟的 erbB2-/- 少突胶质细胞中，它们无法通过形成髓磷脂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中发挥着不可或缺的作用。我们的总体假设是，神经调节蛋白介导的信号在早期、终末分化之前以及少突胶质细胞发育的后期（包括髓鞘形成）都是必需的。具体目标 1 重点关注神经调节蛋白介导的信号在早期少突胶质细胞发育中的功能。这一目标将需要对神经调节蛋白-1、erbB3 和 erbB4 突变小鼠的小鼠脊髓中的 GRP、OPC 和前突胶质细胞进行完整分析。具体目标 2 将确定神经调节蛋白是否发出早期少突胶质细胞发育中的存活与分化信号。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。