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-运动连接模式被认为是硬连线的，但在识别介导输入选择性的表面识别系统方面进展缓慢。众所周知，经典的钙粘蛋白可以根据运动神经元的池身份来描述运动神经元的亚型，而功能的获得和丧失研究已经证明，钙粘蛋白的活性是将运动神经元分类到池中所必需的。本体感觉神经元也表达钙粘蛋白，有证据表明，钙粘蛋白的表达在功能上相互连接的感觉神经元和运动神经元亚群之间具有协调性。这些观察结果提出了与发育相关的钙粘蛋白“匹配代码”的可能性，其中由感觉传入和运动神经元表达的配对钙粘蛋白的亲同性或异性相互作用促进了直接突触特异性的粘附相互作用。本研究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。现有小鼠运动神经元ßγ-cat和N-cad突变体的早期致死率使得无法分析其在感觉-运动连接中的独立作用。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ßγ-cat和钙粘蛋白突变体的感觉-运动连接谱，这些突变体是通过使用更具选择性的cre驱动系产生的，该驱动系允许在脊髓运动神经元的受限亚群中失活靶基因。我们将研究是否选择性破坏

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.