Cadherin-Catenin Based Recognition in Sensory-Motor Connectivity

感觉运动连接中基于钙粘蛋白-连环蛋白的识别

• 批准号: 8630338
• 负责人: Thomas M. Jessell
• 金额: $ 35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630338
• 关键词: Address; Adhesives; Afferent Neurons; Affinity; Anatomy; Animals; Behavior; Binding; Biological Assay; Bypass; Cadherins; Cell Aggregation; Cells; Chinese Hamster Ovary Cell; Code; Complement; Embryo; Family; Felis catus; Foundations; Gene Silencing; Gene Targeting; Individual; Joints; Limb structure; Logic; Longitudinal Studies; Maps; Measurement; Mediating; Molecular; Molecular Analysis; Motor; Motor Neurons; Mus; Mutant Strains Mice; N-Cadherin; Nerve Degeneration; Neurons; Pattern; Physiology; Positioning Attribute; Property; Proprioceptor; Proteins; Rabies; Role; Sensory; Signal Transduction; Sorting - Cell Movement; Specificity; Spinal; Spinal Cord; Spinal cord injury; Staging; Surface; Surface Plasmon Resonance; Synapses; System; Testing; Therapeutic Intervention; base; cell behavior; design; loss of function; member; migration; motor neuron development; mutant; novel; public health relevance; recombinase; research study; sensory mechanism; synaptogenesis

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.

项目摘要 哺乳动物脊髓中的单突触感觉运动连接的模式为 被认为是固定的，但是在识别表面识别方面取得了缓慢的进步 介导输入选择性的系统。众所周知，经典的钙粘蛋白可以描绘运动神经元 亚型根据其池的身份，功能研究的增益和丧失具有 表明，将运动神经元分选为池中需要钙粘蛋白活性。 钙黏着蛋白也通过本体感知性感觉神经元表达，并且有证据表明 通过功能互连的感觉和 运动神经元子集。这些观察结果增加了相关的可能性 cadherin的“匹配代码”，其中配对钙粘蛋白的均电或异质相互作用 由感觉传入和运动神经元表达 突触特异性。 该建议旨在阐明钙粘蛋白识别在感觉运动中的作用 通过分子分析经典钙粘蛋白失活的影响 运动神经元。现有的小鼠运动神经元的早期致死性 - -CAT和N -CAD突变体 已经排除了对感觉运动连通性中独立作用的分析。绕过这一点 问题我们将使用解剖学和生理学来检查感官运动连接曲线 可行的� -cat和cadherin突变体，通过使用更具选择性的CRE驱动线生成 这种允许在受限的脊柱运动神经元子集中灭活靶基因。我们将 检查选择性破坏�CAT，N -CAD或II型钙粘蛋白是单独还是在 组合足以侵蚀感觉电动机连接的保真度。进一步探究 运动神经元钙粘蛋白信号的机制我们将使用细胞结合测定法探索 N-钙粘蛋白与许多II型钙粘蛋白之间相互作用的逻辑和特异性 由运动神经元表达。 总之，这些研究旨在定义突触的分子基础 感觉运动突触的连接性，这是功能的关键早期步骤 电机电路。