Development of Oligodendrocytes in the Spinal cord

脊髓少突胶质细胞的发育

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6753525
• 关键词: Xenopus; axon; biological signal transduction; cell differentiation; cell growth regulation; cell migration; chick embryo; developmental neurobiology; gene expression; gene targeting; genetically modified animals; growth factor receptors; laboratory mouse; nervous system transplantation; neuregulins; neurogenesis; neurons; neurotrophic factors; oligodendroglia; optic nerve; retina; spinal cord; transcription factor; vertebrate embryology

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）：我们已经表明，在特定发育中的特定时间，在脊髓的脊髓腹心室区域出现了少突胶质细胞（CNS的骨髓细胞）的最早前体。拟议的研究将确定少突胶质细胞诱导的细胞和分子调节剂，并定义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Neuregulin（NRG）。当少突胶质细胞前体首次发育时，腹侧脊髓由运动神经元和长轴突段填充，我们最近的研究表明，这些细胞的提示需要诱导少突胶质细胞。我们的工作假设是SHH和NRG必须由神经元或其过程表达，以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由使用视网膜作为缺乏少突胶质细胞的神经元来源的神经元和/或轴突信号诱导。然后，我们将确定神经元诱导是否取决于SHH和NRG，以及是否必须由同一神经元细胞制成NRG和SHH。在第二个目的中，我们将检验以下假设：视网膜轴突信号诱导视神经少突胶质细胞，并确定移植的视网膜是否可以诱导背脊髓中的少突胶质细胞。尽管它们在受限的位置出现，但少突胶质细胞被广泛分布在成年中枢神经系统中。因此，前体必须通过中枢神经系统迁移到髓鞘轴突。我们将检验以下假设：腹腹中线细胞制造的Netrin充当反击提示，以指导少突胶质细胞前体向推定白质的迁移。在第三个目的中，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的化学细胞功能，并在少突胶质细胞前体上鉴定功能性Netrin受体。此外，我们将确定排斥分子（例如缝隙引导少突胶质细胞前体迁移）是否。在第四目的中，我们将比较野生型和Netrin敲除动物的寡胶质细胞前体的分布，以确定在没有Netrin的情况下这些细胞的迁移是否受到干扰。这些研究将提供有关脊椎动物中枢神经系统中寡胶质细胞开发的机制的重要新信息，并将导致新颖的方法在中枢神经系统损伤或脱髓鞘疾病后实现重新延展。