Cadherin-Catenin Based Recognition in Sensory-Motor Connectivity

项目摘要 哺乳动物脊髓中单突触感觉-运动连接的模式是 被认为是硬连接的，但在识别表面识别方面进展缓慢 调节输入选择性的系统。已知经典钙粘附素可描绘运动神经元 根据池的身份和功能的得失进行亚型研究 证明了钙粘附素活性是运动神经元分类所必需的。 钙粘附素也由本体感觉神经元表达，有证据表明 功能上相互联系的感觉与钙粘附素表达谱的协调 运动神经元亚群。这些观察结果提高了一种与发展相关的 钙粘附素配对编码：成对钙粘蛋白的同亲或异亲相互作用 由感觉传入和运动神经元表达促进粘连相互作用 突触专一性。 本提案旨在阐明钙粘附素识别在感觉运动中的作用。 通过分子分析连接经典钙粘附素失活的影响 运动神经元。现有小鼠运动神经元CAT和N-cad突变体的早期致死性 排除了对感觉-运动连接中独立作用的分析。绕过这一点 问题我们将使用解剖学和生理学来检查感觉-运动连接的配置文件 可行的CAT和钙粘素突变体，通过使用更具选择性的cre驱动系产生 这使得脊髓运动神经元的限制性亚群中的靶基因失活。我们会 检查选择性干扰CAT、N-cad或II型钙粘附素是单独还是在 两者的结合足以削弱感觉运动连接的保真度。为了进一步探讨 运动神经元钙粘附素的信号转导机制我们将使用细胞结合分析来探索 N-钙粘附素与多种II型钙粘附素相互作用的逻辑和特异性 由运动神经元表达。 总之，这些研究旨在确定突触的分子基础 感觉-运动突触的连通性，这是建立功能性 马达电路。

Project Summary The pattern of monosynaptic sensory-motor connections in the mammalian spinal cord is thought to be hard-wired, but there has been slow progress in identifying surface recognition systems that mediate input selectivity. Classical cadherins are known to delineate motor neuron subtypes according to their pool identities, and gain and loss of function studies have demonstrated that cadherin activity is required for the sorting of motor neurons into pools. Cadherins are also expressed by proprioceptive sensory neurons, and there is evidence for coordination in the profiles of cadherin expression by functionally interconnected sensory and motor neuron subsets. These observations raise the possibility of a developmentally relevant cadherin 'matching code' in which the homophilic or heterophilic interactions of paired cadherins expressed by sensory afferents and motor neurons promote adhesive interactions that direct synaptic specificity. This proposal aims to clarify the role of cadherin recognition in sensory-motor connectivity through a molecular analysis of the impact of classical cadherin inactivation in motor neurons. The early lethality of existing mouse motor neuron ¿¿-cat and N-cad mutants has precluded analysis of an independent role in sensory-motor connectivity. To bypass this problem we will use anatomy and physiology to examine sensory-motor connectivity profiles in viable ¿¿-cat and cadherin mutants, generated through the use of more selective cre driver lines that permit inactivation of target genes in restricted subsets of spinal motor neurons. We will examine whether selective disruption of ¿¿-cat, N-cad or type II cadherins alone or in combination is sufficient to erode the fidelity of sensory motor connections. To probe further the mechanisms of motor neuron cadherin signaling we will use cell binding assays to explore the logic and specificity of interactions between N-cadherin and the many type II cadherins expressed by motor neurons. Together, these studies are intended to define the molecular basis of synaptic connectivity at sensory-motor synapses, a key early step in the establish ment of functional motor circuits.