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磷脂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，特别是音刺猬，出现必要的规格的谱系，而轴突信号似乎是重要的，在早期和晚期少突胶质细胞的发展。Neuregulin-1定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必需的分子之一。在neuregulin-1的情况下，O 4 + proligodendroblasts不发展脊髓外植体。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原成光突细胞的发育。少突胶质细胞通过激活erbB受体酪氨酸激酶家族的成员对神经调节蛋白作出反应，所述erbB受体酪氨酸激酶家族作为信号转导异源二聚体起作用。我们最近表明，erbB 2受体酪氨酸激酶是不必要的少突胶质细胞前体发育的早期阶段，但proligodendrobytes分化成半乳糖苷脂阳性（GalC+）少突胶质细胞（终末分化）是必不可少的。在erbB 2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erbB 2（erbB 2-/-）的情况下，少突胶质细胞的发育停止在proligodendroblast阶段，Ga 1C+少突胶质细胞的数量减少了10倍以上。少数的erbB 2-/-少突胶质细胞，进行分化成熟，这些不能通过形成髓鞘节间与神经突相互作用。这些数据表明，erbB 2是所需的少突胶质细胞的终末分化和髓鞘形成。我们的数据和其他实验室的数据一起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的不可或缺的作用。我们的总体假设是，neuregulin介导的信号是必要的，在早期，终末分化之前，和少突胶质细胞发育的晚期阶段，包括髓鞘形成。具体目标1集中在神经调节蛋白介导的信号在早期少突胶质细胞发育的功能。这一目标将需要一个完整的分析GRP，OPC和proligodendroblasts在小鼠脊髓神经调节蛋白-1，erbB 3和erbB 4突变小鼠。特异性目标2将确定神经调节蛋白是否在早期少突胶质细胞发育中信号存活与分化。特异性目标3将确定erbB 2、erbB 3或erbB 4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和髓鞘形成的终末分化的轴突信号。

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.