NEUREGULINS IN OLIGODENDROCYTE DEVELOPMENT & MYELINATION

少突胶质细胞发育和髓鞘形成的各个阶段， 近年来被描述。 然而，特定的分子 控制这些事件的机制定义不清。Oligodendrocyte 已经证明，在来自以下的脊髓外植体中发生发育： 胚胎小鼠的时间表，概括了他们的发展， vivo. 我们最近发现少突胶质细胞谱系中的细胞 在早期胚胎neuregulin的脊髓外植体中不能发育 基因敲除小鼠 在这个资助申请中，我们建议使用这个模型 系统来解决假设：1）neuregulins是必要的， 少突胶质细胞谱系的特定发育阶段，2） 神经调节蛋白被呈递给发育中的少突胶质前体细胞 特别是通过神经元或星形胶质细胞，3）神经调节蛋白受体erbB 2 和erbB4是少突胶质细胞谱系发育所必需的， 4)少突胶质细胞发育、髓鞘形成和 髓鞘节间的维持，需要持续存在的 神经调节蛋白，和5）神经调节蛋白激活特异性信号转导 少突胶质细胞系细胞中的信号通路。 这些假设将 使用分子和细胞生物学相结合的方法进行研究， 接近。 将使用神经调节蛋白敲除小鼠来确定 少突胶质细胞谱系的特定沿着阶段受 神经调节蛋白通过添加回外源性神经调节蛋白来拯救谱系。 将神经元或星形胶质细胞与脊髓外植体共培养， 用于确定神经调节蛋白是否被呈递到细胞中， 少突胶质细胞谱系中的细胞特异性的方式。 的重要性 少突胶质细胞发育中的单个神经调节蛋白受体将被 首先在erbB2敲除中研究。神经调节蛋白的抑制剂将是 用于研究神经调节蛋白在髓鞘形成和维持中的作用 的髓鞘节间使用在体外和体内系统。 的 激活的神经调节蛋白受体的物理和功能关联 与细胞内信号分子将在细胞中进行研究， 少突胶质细胞谱系。

The various stages of oligodendrocyte development and myelination have been described in recent years. However, the specific molecular mechanisms controlling these events are poorly defined. Oligodendrocyte development has been shown to occur in spinal cord explants from embryonic mice on a timetable that recapitulates their development in vivo. We have recently found that cells in the oligodendrocyte lineage fail to develop in spinal cord explants from early embryonic neuregulin knock-out mice. In this grant application we propose to use this model system to address the hypotheses that: 1) neuregulins are necessary at specific developmental stages of the oligodendrocyte lineage, 2) neuregulins are presented to developing oligodendrocyte precursor cells specifically by neurons or astrocytes, 3) the neuregulin receptors erbB2 and erbB4 are required for development of the oligodendrocyte lineage, 4) the late events in oligodendrocyte development, myelination and maintenance of the myelin internode, require the continued presence of neuregulins, and 5) neuregulins activate specific signal transduction pathways in cells of the oligodendrocyte lineage. These hypotheses will be studied using a combination of molecular and cell biological approaches. Neuregulin knock-out mice will be used to determine the specific stages along the oligodendrocyte lineage influenced by neuregulins by adding back exogenous neuregulin to rescue the lineage. Co-cultures of neurons or astrocytes with spinal cord explants will be used to determine if neuregulin is presented to cells in the oligodendrocyte lineage in a cell specific manner. The importance of individual neuregulin receptors in oligodendrocyte development will be studied first in the erbB2 knock-out. Inhibitors of neuregulin will be used to study the role neuregulins play in myelination and maintenance of the myelin internode using both in vitro and in vivo systems. The physical and functional association of activated neuregulin receptors with intracellular signaling molecules will be studied in cells of the oligodendrocyte lineage.