Cadherin-Catenin Based Recognition in Sensory-Motor Connectivity

描述（由申请人提供）：哺乳动物脊髓中的单突触感觉-运动连接的模式被认为是硬连线的，但是在鉴定介导输入选择性的表面识别系统方面进展缓慢。已知经典钙粘蛋白根据其池身份描绘运动神经元亚型，并且功能的获得和丧失研究已经证明，钙粘蛋白活性是将运动神经元分选到池中所需的。钙粘蛋白也表达本体感觉神经元，有证据表明，协调功能相互关联的感觉和运动神经元亚群的钙粘蛋白表达的配置文件。这些观察结果提出了一个发展相关的钙粘蛋白“匹配代码”的可能性，其中感觉传入和运动神经元表达的成对钙粘蛋白的嗜同性或嗜异性相互作用促进直接突触特异性的粘附相互作用。该提案旨在通过对经典钙粘蛋白失活对运动神经元的影响进行分子分析，阐明钙粘蛋白识别在感觉-运动连接中的作用。现有的小鼠运动神经元β γ-cat和N-cad突变体的早期致死性已经排除了在感觉-运动连接中的独立作用的分析。为了绕过这个问题，我们将使用解剖学和生理学来检查可行的γ-cat和钙粘蛋白突变体中的感觉-运动连接概况，这些突变体是通过使用更具选择性的cre驱动系产生的，这些驱动系允许脊髓运动神经元的有限子集中的靶基因失活。我们将研究是否有选择地破坏 γ-cat、N-cad或II型钙粘蛋白单独或组合足以侵蚀感觉运动连接的保真度。为了进一步探索运动神经元钙粘蛋白信号转导的机制，我们将使用细胞结合试验来探索N-钙粘蛋白和运动神经元表达的许多II型钙粘蛋白之间相互作用的逻辑和特异性。总之，这些研究旨在确定感觉-运动突触突触连接的分子基础，这是建立功能性运动回路的关键早期步骤。

DESCRIPTION (provided by applicant): 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 ßγ-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 ßγ-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 ßγ-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.