THE FnA D REGION OF TENASCIN C AND NEURONAL GROWTH

腱蛋白 C 的 FNA D 区域与神经元生长

• 批准号: 6540302
• 负责人: SALLY A MEINERS
• 金额: $ 31.4万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540302
• 关键词: RNA splicing; affinity chromatography; chemoattractants; chondroitin sulfates; developmental neurobiology; fibronectins; gene targeting; genetically modified animals; integrins; laboratory mouse; neurogenesis; neuronal guidance; protein isoforms; protein structure function; proteoglycan; tenascin

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.

描述（来自申请人的摘要）：我们研究的总体目标是 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。该提案的重点是了解如何 细胞外基质分子生腱蛋白-C 调节神经元生长。 Tenascin-C 不是单个分子，而是一个替代分子家族 含有不同 III 型纤连蛋白组合的剪接变体 域。我们发现生腱蛋白-C 区域仅含有 交替剪接的 III 型纤连蛋白结构域，称为 fnA-D，当使用时 其本身显着增加了培养物中神经突的生长。事实上，这 分子是我们在测试中发现的最有效的生长促进剂 文化。选择性剪接区域还提供了方向线索 生长的神经突，我们将其定义为神经突引导。神经突表现出 当他们在界面上进行选择时，他们会强烈偏爱 fbA-D。 FnA-D 甚至影响延伸到通常排斥的硫酸软骨素 蛋白多糖是神经胶质疤痕中的主要抑制分子。我们有 将这些特征与 fnA-D 分子的不同域相关联： fnD（第七种纤连蛋白 III 型）促进神经突生长 域），以及 fnC（第六域）的神经突引导。更具体地说，我们 进一步将生长活性定位于 fnD 内的 8 个氨基酸 29-36 我们称之为“生长促进基序”（OPM）。我们也确定了 针对 OPM 的抗体可以通过以下方式减少神经突生长 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神经突的假设 fnA-D 介导的生长和神经突引导是不同的过程，每个过程 其中可以独立操纵以鼓励定向神经元 再生。此外，我们将探讨以下假设： 生腱蛋白-C 可能具有作为可溶性化学引诱剂分子的特性。