Development of Oligodendrocytes in the Spinal cord

脊髓少突胶质细胞的发育

基本信息

批准号：
6753525
负责人：
ROBERT H. MILLER
金额：
$ 32.7万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-01-01 至 2007-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We have shown that the earliest precursors for oligodendrocytes (the myelinating cells of the CNS) arise in the ventral ventricular region of the spinal cord at a particular time in development. The proposed studies will identify the cellular and molecular regulators of oligodendrocyte induction and define the guidance cues that control the directional migration of oligodendrocyte precursors. The ventral origin of oligodendrocytes depends on local environmental signals that include sonic hedgehog (Shh) and neuregulin (NRG). When oligodendrocyte precursors first arise in development, the ventral spinal cord is populated by motor neurons and long axon tracts, and our recent studies suggests that cues from these cells are required to induce oligodendrocytes. Our working hypothesis is that Shh and NRG must be expressed by neurons or their processes in order to generate oligodendrocyte precursors. In the first aim we will determine whether spinal cord oligodendrocytes can be induced by neuronal and/or axonal signals using retina as a source of neurons that lacks oligodendrocytes. We will then determine if neuronal induction is dependent on Shh and NRG and whether NRG and Shh have to be made by the same neuronal cell. In the second aim we will test the hypothesis that optic nerve oligodendrocytes are induced by signals from retinal axons and determine whether transplanted retina can induce oligodendrocytes in dorsal spinal cord. Although they arise in restricted locations, oligodendrocytes are widely distributed in the adult CNS. Thus the precursors must migrate through the CNS in order to myelinate axonal tracts. We will test the hypothesis that netrin, made by ventral midline cells, acts as a repulsive cue to guide the migration of oligodendrocyte precursors to presumptive white matter. In the third aim we will examine the expression of netrin-1 in the developing spinal cord, and use in vitro migration assays to show the chemorepellant function of netrin and identify functional netrin receptors on oligodendrocyte precursors. In addition, we will determine whether repulsive molecules such as slit guide oligodendrocyte precursor migration. In the forth aim we will compare the distribution of oligodendrocyte precursors in the optic system and spinal cord of wild type and netrin knockout animals to determine whether the migration of these cells is perturbed in the absence of netrin. These studies will provide important new information on the mechanisms underlying oligodendrocyte development in the vertebrate CNS, and will lead to novel approaches to achieve remvelination after CNS injury or demyelinating diseases.

描述（由申请人提供）：我们已经证明，少突胶质细胞（中枢神经系统的髓鞘形成细胞）的最早前体在发育的特定时间出现在脊髓的腹侧心室区域。拟议的研究将确定少突胶质细胞诱导的细胞和分子调节因子，并确定控制少突胶质细胞前体定向迁移的指导线索。少突胶质细胞的腹侧起源取决于局部环境信号，包括声波刺猬 (Shh) 和神经调节蛋白 (NRG)。当少突胶质细胞前体在发育过程中首次出现时，腹侧脊髓充满运动神经元和长轴突束，我们最近的研究表明，需要来自这些细胞的信号来诱导少突胶质细胞。我们的工作假设是，Shh 和 NRG 必须由神经元或其过程表达才能产生少突胶质细胞前体。在第一个目标中，我们将确定脊髓少突胶质细胞是否可以通过使用视网膜作为缺乏少突胶质细胞的神经元来源来由神经元和/或轴突信号诱导。然后我们将确定神经元诱导是否依赖于 Shh 和 NRG，以及 NRG 和 Shh 是否必须由同一神经元细胞产生。在第二个目标中，我们将测试视神经少突胶质细胞是由来自视网膜轴突的信号诱导的假设，并确定移植的视网膜是否可以在背脊髓中诱导少突胶质细胞。尽管少突胶质细胞出现的位置有限，但它们广泛分布在成人中枢神经系统中。因此，前体细胞必须迁移通过中枢神经系统才能使轴突束有髓鞘化。我们将检验这样的假设：由腹侧中线细胞产生的netrin充当排斥线索，引导少突胶质细胞前体迁移到假定的白质。在第三个目标中，我们将检查 netrin-1 在发育中的脊髓中的表达，并使用体外迁移测定来显示 netrin 的化学排斥功能并鉴定少突胶质细胞前体上的功能性 netrin 受体。此外，我们将确定诸如狭缝之类的排斥分子是否引导少突胶质细胞前体迁移。在第四个目标中，我们将比较野生型和 netrin 敲除动物的视觉系统和脊髓中少突胶质细胞前体的分布，以确定这些细胞的迁移在缺乏 netrin 的情况下是否受到干扰。这些研究将为脊椎动物中枢神经系统少突胶质细胞发育的机制提供重要的新信息，并将导致中枢神经系统损伤或脱髓鞘疾病后实现修复的新方法。