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、呼吸和 平衡，依靠脊髓内神经元建立选择性连接的能力 发展。过去十年的工作提供了一个相当全面的了解 决定神经管内每个主要神经元类别的身份的遗传路径。这个 神经元获得亚型身份的机制，这是整合到 然而，对特定马达电路的定义仍然很模糊。我们对脊柱规范的研究 运动神经元表明，HOX转录因子大家族在产生 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不同方面的遗传程序，包括它们的地形 组织、外周靶肌肉特异性和突触前伙伴。新兴的研究来自 我们的研究小组还指出，HOX基因在多个神经元类别中发挥作用，以形成突触 在发育过程中的特异性，表明在电路组装中发挥更广泛的作用。《公约》的总体目标 建议的研究是为了阐明神经多样化和内部连接的机制 脊髓，并确定HOX依赖和独立的遗传程序如何建立 电机控制所需的电路结构。最终，我们希望发现这些路径 通过这种方式，基因编码的发育程序有助于出现特定的 运动行为。我们的方法集成了对神经元亚型的选择性遗传操作， 调节网络的全基因组询问，现代电路追踪方法，比较 对多种脊椎动物的分析，以及对行为的严格分析。阐明基本的 电机电路装配的机理将提供与设计相关的基本见解 治疗脊髓神经元退行性疾病或修复运动神经回路的治疗策略 因受伤而受损的。

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.