AXONAL GROWTH CONE SIGNAL TRANSDUCTION

描述(摘自申请者摘要)：远端的生长锥体 伸展轴突的顶端是一种特殊的感觉器官，它能 细胞外信号沿着适当的途径进入生长纠正 突触靶标。它的正常功能对神经系统发育至关重要。 从而影响成人神经系统的表现。这个应用程序寻找一个分子 了解神经元生长过程中的信号转导机制 圆锥体。特别强调的是Semaphorin家族的行动 最近发现的抑制轴突延伸和终末的蛋白质 树木化。 这个实验室和其他实验室之前的工作导致了这样的理解 3类信号素与细胞表面的神经粘连蛋白结合，并且 信号素/神经粘连蛋白复合体激活网络蛋白跨膜多肽 启动细胞内信号转导级联反应。这个生长锥体 排斥性信号转导通路涉及GTP结合蛋白Rac1和CRMPs。 其他类别的信号素直接激活丛状蛋白，而不是神经粘连蛋白 参与其中。在这里，我们试图在几个方向上扩展这一理解。 鉴于由20个成员组成的Semaphorin家族影响着许多生物事件 而且丛状蛋白家族至少有9个成员，作用的特异性是 关键问题。配体/受体配对和生物学功能将 探索了3类和4类信号素以及各种丛状蛋白。分子 下游元件，即Rac1和CRMP的功能是 由丛状蛋白的胞内结构域改变的将通过 蛋白质结合研究、酶分析和细胞形态的结合 化验。我们将研究这一信号转导的调制，通过 配体/受体聚集和受体蛋白酪氨酸磷酸酶(RPTP) 丛状蛋白磷酸化的调控。 总的来说，这些实验应该提供了对 生长锥对细胞外反应的分子事件 令人厌恶的信号，如信号素。对这些途径的了解将取决于 理解人类病理生理学的必要基础 大脑发育异常。同样的机制很可能会 在成人神经系统再生和可塑性过程中的作用，使 对这些系统的药理调节可能会在 创伤性损伤和改善退行性神经疾病的功能。

DESCRIPTION (Adapted from applicant's abstract): The growth cone at the distal tip of the extending axon is a specialized sensory apparatus that transduces extracellular signals into growth along appropriate pathways to correct synaptic targets. Its proper function is crucial to nervous system development and hence adult nervous system performance. This application seeks a molecular understanding of the signal transduction mechanisms at the neuronal growth cone. Particular emphasis is focused on the action of the Semaphorin family of proteins recently recognized to inhibit axonal extension and terminal arborization. Previous work from this laboratory and others has led to the understanding that class 3 Semaphorins bind to cell surface Neuropilins and that a Semaphorin/Neuropilin complex activates a Plexin transmembrane polypeptide to initiate an intracellular signal transduction cascade. This growth cone repulsive transduction cascade involves the GTP-binding protein racl and CRMPs. Other classes of Semaphorins activate Plexins directly, without Neuropilin involvement. Here, we seek to extend this understanding in several directions. Given that the 20-member Semaphorin family affects numerous biological events and that the Plexin family has at least 9 members, specificity of action is a crucial issue. Ligand/receptor pairing and biological functions will be explored for the class 3 and 4 Semaphorins and various Plexins. The molecular mechanisms whereby the function of downstream elements, racl and CRMP, is altered by the intracellular domain of Plexin will be investigated through a combination of protein binding studies, enzymatic assays and cell morphology assays. We will examine the modulation of this signal transduction both by ligand/receptor clustering and by receptor protein tyrosine phosphatase (RPTP) control of Plexin phosphorylation. Together these experiments should provide a detailed description of the molecular events that underlie growth cone responsiveness to extracellular repulsive signals such as the Semaphorins. Knowledge of these pathways will lay the necessary groundwork for understanding the pathophysiology of human developmental abnormalities of the brain. The same mechanisms are likely to function during adult nervous system regeneration and plasticity, so that pharmacological modulation of these systems may potentiate recovery after traumatic injury and improve function in degenerative neurologic diseases.