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: 6331023
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6331023
• 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 为了了解神经元的生长是如何通过与 细胞外基质分子该建议的核心是了解如何 细胞外基质分子生腱蛋白-C调节神经元生长。 生腱蛋白-C不是一个单一的分子，而是一个家族， 含有III型纤连蛋白的不同组合的剪接变体 域.我们已经发现，腱生蛋白-C的仅含有 交替剪接的纤连蛋白III型结构域，称为fnA-D，当用于 本身，在培养中显著增加神经突生长。其实这 分子是最有效的生长促进剂，我们已经确定在我们的测试， 文化交替拼接区域还提供方向线索， 我们称之为神经突引导神经突表现出 当在接口处给予它们选择时，强烈偏好fbA-D。FnA-D 甚至影响延伸成通常排斥的硫酸软骨素 蛋白聚糖，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： 用fnD（第七种纤连蛋白III型）促进神经突生长 第六，引导引导，引导。更具体地说， 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）。我们还确定 针对OPM的抗体可以通过以下方式减少神经突生长： 腱生蛋白-C，从而证明该区域在完整的细胞内是功能性的。 分子。因此，我们最初的目标是探索神经突 由fnA-D介导的生长和轴突导向是不同的过程， 可以独立地操作，以促进定向神经元 再生此外，我们将探讨的假设，这些领域的 生腱蛋白-C可以具有作为可溶性化学引诱物分子的性质。