ROLE OF CD44 IN PERIPHERAL NERVE DEVELOPMENT AND INJURY

这些研究的主要目的是阐明CD44跨膜糖蛋白家族在周围神经发育和损伤后的作用。周围神经的发育和维持需要轴突和雪旺细胞之间严格调节的相互作用。雪旺细胞的存活、增殖和分化受轴突源性信号的影响。其中一个关键信号是胶质生长因子（GGF），它激活雪旺细胞中酪氨酸受体蛋白激酶erbB2和erbB3的异源二聚体。GGF及其受体也与沃勒氏变性有关，这是一种神经损伤后发生的过程，包括诱导雪旺细胞增殖。GGF和相关轴突衍生信号促进erbB2-erbB3异源二聚化和激酶活性的途径尚不清楚。我们的中心假设是CD44蛋白是GGF信号和雪旺细胞存活、增殖和分化所必需的。CD44参与细胞-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递呈。我们的初步数据表明，CD44对雪旺细胞erbB2-erbB3异源二聚化至关重要，抑制CD44的表达可导致雪旺细胞凋亡。我们还发现，当erbB2高表达和雪旺细胞增殖活跃时，CD44在发育中的周围神经中也有高水平表达。我们认为CD44通过促进轴突衍生的GGF和雪旺细胞表面的erbB受体之间的相互作用而起作用。我们将通过以下具体目标对这一概念进行实验验证：(1)确定CD44是否作为低亲和力的GGF受体；(2)利用表达突变CD44蛋白的细胞确定介导与ErbB2和ErbB3相互作用的CD44结构域；(3)通过比较野生型小鼠和转基因小鼠的雪旺细胞缺乏CD44，确定周围神经发育和沃勒氏变性过程中雪旺细胞的存活、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，将有助于了解正常周围神经发育的分子机制，并可能有助于我们理解轴突变性发生的许多病症和疾病，包括神经创伤、脊髓损伤和周围神经病变。

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.