ROLE OF CD44 IN PERIPHERAL NERVE DEVELOPMENT AND INJURY

CD44 在周围神经发育和损伤中的作用

• 批准号: 6874658
• 负责人: Larry S. Sherman
• 金额: $ 2.49万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-17 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874658
• 关键词: CD44 molecule; Schwann cells; cell differentiation; cell proliferation; enzyme activity; genetically modified animals; growth factor receptors; intermolecular interaction; laboratory mouse; nerve injury; nervous system regeneration; neurogenesis; neurotrophic factors; peripheral nervous system; protein tyrosine kinase; wallerian degeneration

The principle goal of the proposed studies is to elucidate the role of the CD44 family of transmembrane glycoproteins in perpheral nerves during development and following injury. Peripheral nerve development and maintenance require tightly regulated interactions between axons and Schwann cells. Schwann cell survival, proliferation and differentiation are influenced by axon-derived signals. One key signal is glial growth factor (GGF), which activates heterodimers of the receptor protein tyrosine kinases erbB2 and erbB3 in Schwann cells. GGF and its receptors have also been implicated in Wallerian degeneration, a process that occurs following nerve injury and which includes that induction of Schwann cell proliferation. The means by which GGF and related axon-derived signals promote erbB2-erbB3 heterodimerization and kinase activity are unclear. Our central hypothesis is that CD44 proteins are required for GGF signaling and in Schwann cell survival, proliferation and differentiation. CD44 has been implicated in cell-cell and cell- matrix interactions, and in growth factor presentation to high affinity cell surface receptors. Our preliminary data indicate the CD44 is essential for erbB2-erbB3 heterodimerization in Schwann cells, and that inhibition of CD44 expression results in Schwann cell apoptosis. We also found that CD44 is expressed in developing peripheral nerve at high levels when erbB2 expression is high and during active Schwann cell proliferation. We propose that CD44 acts by facilitating the interaction between axon- derived GGF and erbB receptors on the Schwann cell surface. We will test this notion experimentally with the following specific aims: (1) To ascertain whether CD44 acts as a low affinity GGF receptor; (2) To define the structural domains of CD44 that mediate interactions with ErbB2 and ErbB3 using cells expressing mutant CD44 proteins; (3) To determine if CD44 is required for Schwann cell survival, proliferation and/or differentiation during peripheral nerve development and Wallerian degeneration by comparing wild type mice and trasngenic mice whose Scwann cells lack CD44. Understanding how CD44 mediates the GGF-erbB2-erbB3 signaling complex will provide insight into the molecular mechanisms underlying normal peripheral nerve development, and may contribute significantly to our understanding of numerous conditions and diseases where axonal degeneration occurs, including nerve trauma, spinal cord injuries, and peripheral neuropathies.

拟议研究的主要目标是阐明跨膜糖蛋白 CD44 家族在发育和损伤后周围神经中的作用。周围神经的发育和维持需要严格调节轴突和雪旺细胞之间的相互作用。 雪旺细胞的存活、增殖和分化受到轴突衍生信号的影响。 一个关键信号是神经胶质生长因子 (GGF)，它可激活雪旺细胞中受体蛋白酪氨酸激酶 erbB2 和 erbB3 的异二聚体。 GGF 及其受体也与沃勒变性有关，沃勒变性是神经损伤后发生的过程，其中包括诱导雪旺细胞增殖。 GGF 和相关轴突衍生信号促进 erbB2-erbB3 异二聚化和激酶活性的方式尚不清楚。我们的中心假设是 CD44 蛋白是 GGF 信号传导以及雪旺细胞存活、增殖和分化所必需的。 CD44 与细胞-细胞和细胞-基质相互作用以及生长因子向高亲和力细胞表面受体的呈递有关。 我们的初步数据表明，CD44 对于施万细胞中的 erbB2-erbB3 异二聚化至关重要，并且抑制 CD44 表达会导致施万细胞凋亡。 我们还发现，当 erbB2 表达高且雪旺细胞增殖活跃时，CD44 在发育中的周围神经中表达高水平。 我们认为 CD44 通过促进雪旺细胞表面上轴突衍生的 GGF 和 erbB 受体之间的相互作用来发挥作用。 我们将通过实验检验这一概念，具体目的如下：（1）确定CD44是否作为低亲和力GGF受体发挥作用； (2) 使用表达突变型 CD44 蛋白的细胞来定义介导与 ErbB2 和 ErbB3 相互作用的 CD44 的结构域； (3)通过比较野生型小鼠和斯旺细胞缺乏CD44的转基因小鼠，确定周围神经发育和华勒变性过程中施旺细胞的存活、增殖和/或分化是否需要CD44。了解 CD44 如何介导 GGF-erbB2-erbB3 信号复合物将有助于深入了解正常周围神经发育的分子机制，并可能对我们了解轴突变性发生的多种病症和疾病有重大贡献，包括神经创伤、脊髓损伤和周围神经病变。

项目成果

Coordinate control of axon defasciculation and myelination by laminin-2 and -8.

• DOI: 10.1083/jcb.200411158
• 发表时间: 2005-02-14
• 期刊: The Journal of cell biology
• 作者: Yang D;Bierman J;Tarumi YS;Zhong YP;Rangwala R;Proctor TM;Miyagoe-Suzuki Y;Takeda S;Miner JH;Sherman LS;Gold BG;Patton BL
• 通讯作者: Patton BL