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.

项目概要 哺乳动物脊髓中单突触感觉运动连接的模式是 被认为是硬连线的，但在识别表面识别方面进展缓慢 调节输入选择性的系统。已知经典钙粘蛋白可描绘运动神经元 根据其池身份进行亚型，以及功能的获得和丧失研究 证明钙粘蛋白活性是将运动神经元分类到池中所必需的。 钙粘蛋白也由本体感觉感觉神经元表达，并且有证据表明 通过功能上相互关联的感觉和功能来协调钙粘蛋白表达谱 运动神经元亚群。 这些观察结果提出了一种与发展相关的可能性 钙粘蛋白“匹配代码”，其中配对钙粘蛋白的同性或异性相互作用 由感觉传入和运动神经元表达，促进粘附相互作用，从而指导 突触特异性。 该提案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来确定连通性 运动神经元。 现有小鼠运动神经元 ¿¿-cat 和 N-cad 突变体的早期致死率 排除了对感觉运动连接中独立作用的分析。 为了绕过这个 为了解决这个问题，我们将使用解剖学和生理学来检查感觉运动连接概况 可行的 ¿¿-cat 和钙粘蛋白突变体，通过使用更具选择性的 cre 驱动系产生 允许脊髓运动神经元的受限亚群中的靶基因失活。 我们将 检查是否选择性破坏 ¿-cat、N-cad 或 II 型钙粘蛋白单独或在 组合足以削弱感觉运动连接的保真度。为进一步探究 运动神经元钙粘蛋白信号传导机制我们将使用细胞结合测定来探索 N-钙粘蛋白和许多 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。 这些研究共同旨在定义突触的分子基础 感觉运动突触的连接，这是建立功能性神经元的关键早期步骤 电机电路。