THE FnA D REGION OF TENASCIN C AND NEURONAL GROWTH

描述(摘自申请者摘要)：我们研究的总体目标是 为了了解神经元的生长是如何通过相互作用来调节的 细胞外基质分子。这项建议的核心是了解如何 细胞外基质分子Tenascin-C调节神经元生长。 Tenascin-C不是一个单一的分子，而是一个家族 含有不同组合的纤维连接蛋白III的剪接变异体 域名。我们发现Tenascin-C的区域只包含 交替剪接的纤维连接蛋白III型结构域，称为FNA-D，当由 本身，极大地增加了培养中的轴突生长。事实上，这一点 分子是我们在测试中确定的最有效的生长促进剂 文化。可选的剪接区还提供方向提示 生长中的轴突，我们将其定义为轴突指导。神经突起表现为 当他们在界面上有选择时，他们强烈倾向于FBA-D。FNA-D 甚至影响延伸到通常排斥的硫酸软骨素 蛋白多糖，胶质瘢痕中的主要抑制分子。我们有 将这些特征与FNA-D分子的不同结构域相关联： FND(第七型纤维连接蛋白III型)促进轴突生长 领域)，以及用FNC引导神经突起(第六领域)。更具体地说，我们 进一步将生长活性定位于FND中的8个氨基酸29-36 这就是我们所说的“促进生长”(OPM)。我们还确定了 针对OPM的抗体可以通过以下方式减少轴突生长 Tenascin-C，从而证明该区域在完整的 分子。因此，我们最初的目标是探索轴突的假设 FNA-D介导的突起生长和轴突引导是两个不同的过程 它们可以被独立地操纵以鼓励定向神经元 重生。此外，我们还将探讨以下假设：这些领域 Tenascin-C可能具有作为可溶性趋化分子的性质。

DESCRIPTION (From the Applicant's Abstract): The overall aim of our research is to understand how the growth of neurons is modulated by interaction with extracellular matrix molecules. This proposal centers upon understanding how the extracellular matrix molecule tenascin-C regulates neuronal growth. Tenascin-C is not a single molecule, but is instead a family of alternatively spliced variants containing different combinations of fibronectin type III domains. We have found that the region of tenascin-C containing only the alternately spliced fibronectin type III domains, called fnA-D, when used by itself, dramatically increases neurite outgrowth in culture. In fact, this molecule is the most potent growth promoter we have identified in our tests in culture. The alternatively spliced region also provides directional cues to growing neurites, which we define as neurite guidance. Neurites demonstrate a strong preference for fbA-D when they are given a choice at an interface. FnA-D even influences extension into normally repulsive chondroitin sulfate proteoglycans, the major inhibitory molecules in the glial scar. We have associated these features with different domains of the fnA-D molecule: promotion of neurite outgrowth with fnD (the seventh fibronectin type III domain), and neurite guidance with fnC (the sixth domain). More specifically we further localized the outgrowth activity to the 8 amino acids 29-36 within fnD which we call the "outgrowth promoting motif" (OPM). We have also determined that an antibody directed against the OPM can reduce neurite outgrowth by tenascin-C, thus demonstrating that this region is functional within the intact molecule. Our initial goal is thus to explore the hypothesis that neurite outgrowth and neurite guidance mediated by fnA-D are distinct processes, each of which can be manipulated independently to encourage directed neuronal regrowth. In addition, we will explore the hypothesis that these domains of tenascin-C may have properties as soluble chemoattractant molecules.