AXONAL GROWTH CONE SIGNAL TRANSDUCTION

描述（改编自申请人摘要）：远端的生长锥 延伸轴突的尖端是一种专门的感觉器官， 细胞外信号进入生长沿着适当的途径，以纠正 突触靶点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。本申请寻求分子 了解神经元生长过程中的信号转导机制 浓特别强调的是集中在脑信号蛋白家族的行动， 最近发现的抑制轴突延伸和末端的蛋白质 树枝化 这个实验室和其他实验室的先前工作已经导致了这样的理解， 第3类脑信号蛋白与细胞表面神经纤毛蛋白结合， 脑信号蛋白/神经纤毛蛋白复合物激活丛状蛋白跨膜多肽， 启动细胞内信号转导级联。这个生长锥 排斥性转导级联涉及GTP结合蛋白rac 1和CRMP。 其他类别的脑信号蛋白直接激活丛蛋白，而不需要神经纤毛蛋白 参与。在这里，我们试图在几个方向上扩展这种理解。 鉴于20个成员的脑信号蛋白家族影响许多生物事件， 并且丛状蛋白家族至少有9个成员，作用的特异性是一个 关键问题。配体/受体配对和生物学功能将在 探索了3类和4类信号蛋白和各种丛蛋白。分子 下游元件racl和CRMP的功能通过这些机制被调节， 通过细胞内结构域的丛状蛋白改变将通过一个研究， 结合蛋白结合研究、酶测定和细胞形态学 测定。我们将通过以下两种方法来研究这种信号转导的调节： 配体/受体聚集和受体蛋白酪氨酸磷酸酶（RPTP） 丛状蛋白磷酸化的控制。 这些实验应该一起提供了一个详细的描述 生长锥对细胞外 排斥信号如脑信号蛋白对这些途径的了解 了解人类疾病的病理生理学的必要基础 大脑发育异常同样的机制也可能 在成人神经系统再生和可塑性过程中发挥作用，因此， 这些系统的药理学调节可以增强恢复后 创伤性损伤和改善退行性神经系统疾病的功能。

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.