Genetic Control of Circuit Assembly in the Vertebrate Spinal Cord

项目摘要 控制对哺乳动物至关重要的运动行为的神经回路，包括行走，呼吸， 平衡，依赖于脊髓内神经元的能力，以建立选择性连接， 发展过去十年的工作提供了对 决定神经管内每个主要神经元类别身份的遗传途径。的 神经元获得亚型身份所需的机制， 然而，特定的电动机电路仍然不好定义。我们对脊椎动物规格的研究 运动神经元表明，Hox转录因子大家族在产生运动神经元中起关键作用。 肌肉选择性神经支配所需的数百种亚型。Hox蛋白协调 控制运动神经元成熟的各个方面的遗传程序，包括它们的地形 组织、外周靶肌肉特异性和突触前伙伴。新兴研究， 我们的研究小组还表明，Hox基因在多种神经元中起作用， 发展过程中的特异性，这表明在电路组装更广泛的作用。的总体目标 拟议的研究是阐明神经多样化和连接的机制， 脊髓，并确定如何Hox依赖性和非依赖性的遗传程序建立 电机控制所需的电路结构。最终，我们希望能够揭示 通过这些基因编码的发育程序， 运动行为。我们的方法整合了神经元亚型的选择性遗传操作， 调控网络的全基因组询问，现代电路追踪方法，比较 在多种脊椎动物有机体中的分析，以及对行为的严格分析。阐明基本的 电机电路组装的机制将提供与设计相关的基础见解 治疗脊髓神经元退行性疾病或修复运动回路的治疗策略 因受伤而受损。

Project Summary The neural circuits controlling motor behaviors vital to mammals, including walking, breathing, and balance, rely on the ability of neurons within the spinal cord to establish selective connections during development. Work over the past decade has provided a fairly comprehensive understanding of the genetic pathways that determine the identity of each major neuronal class within the neural tube. The mechanisms through which neurons acquire subtype identities necessary for the incorporation into a particular motor circuit are, however, still poorly defined. Our studies on the specification of spinal motor neurons indicate that the large family of Hox transcription factors play key roles in generating the hundreds of subtypes required for selective innervation of muscle. Hox proteins orchestrate genetic programs that control diverse aspects of motor neuron maturation, including their topographic organization, peripheral target muscle specificity, and presynaptic partners. Emerging studies from our group also indicate that Hox genes function in multiple neuronal classes to shape synaptic specificity during development, suggesting a broader role in circuit assembly. The overall goals of the proposed research are to elucidate the mechanisms of neural diversification and connectivity within the spinal cord, and to determine how Hox-dependent and -independent genetic programs establish the circuit architectures necessary for motor control. Ultimately, we hope to uncover the pathways through which genetically encoded developmental programs contribute to the emergence of specific motor behaviors. Our approach integrates selective genetic manipulations of neuronal subtypes, genome-wide interrogation of regulatory networks, modern circuit-tracing methods, comparative analyses in multiple vertebrate organisms, and rigorous analyses of behavior. Elucidating the basic mechanisms of motor circuit assembly will provide foundational insights relevant to the design of therapeutic strategies to treat degenerative diseases of spinal neurons or repair motor circuits damaged by injury.