Control of Motor Neuron Differentiation

运动神经元分化的控制

• 批准号: 8282733
• 负责人: Thomas M. Jessell
• 金额: $ 34.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282733
• 关键词: Afferent Neurons; Alleles; Behavior; Behavioral; Biological Assay; Characteristics; Degenerative Disorder; Elements; Exhibits; Flexor; Future; Genes; Individual; Injury; Interneurons; Limb structure; Link; Maintenance; Methods; Molecular; Molecular Genetics; Monitor; Motor; Motor Neuron Disease; Motor Neurons; Motor output; Movement; Mus; Muscle; Mutant Strains Mice; Neonatal; Nerve; Neurodegenerative Disorders; Output; Pattern; Physiological; Positioning Attribute; Preparation; Proprioceptor; Proteins; Recovery of Function; Reflex action; Research; Role; Sensory; Specific qualifier value; Specificity; Spinal; Spinal Cord; Spinal cord injury; base; cohort; design; forging; forkhead protein; insight; kinematics; molecular marker; muscle form; mutant; nerve supply; neuromuscular; neuronal cell body; programs; public health relevance; research study; response

DESCRIPTION (provided by applicant): Hox proteins and their transcriptional co-factors have crucial roles in specifying motor neuron identity but their role in directing the assembly of sensory-motor circuits remains less clear. This proposal takes advantage of the discovery that the forkhead transcription factor FoxP1 gates the output of the entire motor neuron Hox repertoire, and determines the subtype identity of spinal motor neurons. We will use motor neuron-specific FoxP1 mutant mice to probe three aspects of the way in which motor neuron pool specification nucleates the organization and function of this prototypic mammalian sensory- motor circuit. First, we will explore the role of Hox/FoxP1 programming in the formation and maintenance of topographic motor projections to target limb muscles. Anatomical tracing methods will be used to define the intraspinal position of lumbar motor neurons that innervate specific limb muscle targets in the absence of FoxP1 function, asking whether motor neuron cell bodies that innervate a given muscle target are positioned randomly within the limb-innervating cohort. In addition, we will use physiological recording and kinematic analyses to assess muscle activity patterns and locomotor behavior in mice in which motor neuron Hox/FoxP1 programming has been abolished. Second, we will examine how the loss of motor pool identity influences patterns of proprioceptive sensory connectivity. Anatomical tracing and physiological recordings from spinal motor neurons will compare the profile of monosynaptic connections between antagonist pairs of sensory and motor neurons in control and motor neuron-specific FoxP1 mutant mice. In parallel, we will determine the impact of loss of motor pool identity on the molecular specification of subsets of proprioceptive sensory neuron that supply individual limb muscles. Third, we will examine how the loss of motor pool identity in FoxP1 mutants perturbs the selectivity of assembly of local inhibitory circuits. Physiological studies will determine how the pattern of connectivity of Ia inhibitory interneurons with motor neurons is altered in motor neuron specific FoxP1 mutants. Molecular markers will be used to identify Ia inhibitory interneurons and examine how the erosion of motor pool identity influences the output and connectivity of this set of interneurons. Together, these studies are intended to forge a link between molecular programs of motor circuit assembly and the behavioral output of these circuits. In the long term, these insights should aid in the design of more effective strategies for promoting functional recovery of spinal circuits after traumatic spinal cord injury, and in motor neuron degenerative diseases. PUBLIC HEALTH RELEVANCE: The activity of spinal motor neuron circuits is critical for movement, and damage to these circuits - through traumatic injury or in neurodegenerative disease - is a major fiscal and societal burden. The research outlined in this proposal aims to define the cellular and molecular mechanisms that control the organization of spinal motor circuits, opening the way for more rational approaches to the treatment of spinal cord injury and motor neuron diseases.

描述（由申请人提供）：HOX蛋白及其转录共同因素在指定运动神经元的身份中具有至关重要的作用，但是它们在指导感觉运动电路组装时的作用仍然不太清楚。该提案利用了发现的发现，即叉子转录因子FOXP1大门扇动了整个电动机神经元HOX曲目的输出，并确定了脊柱运动神经元的亚型身份。我们将使用运动神经元特异性的FOXP1突变小鼠探测运动神经元池规范对该原型哺乳动物感觉 - 运动电路的组织和功能的三个方面。 首先，我们将探讨HOX/FOXP1编程在形成和维护地形运动投影以靶向肢体肌肉中的作用。解剖学示踪方法将用于定义在没有FOXP1功能的情况下支配特定的肢体肌肉靶标的腰运动神经元的脊柱内位置，询问是否支配给定肌肉靶的运动神经元细胞体是否在肢体内接合内随机定位。此外，我们还将使用生理记录和运动学分析来评估运动神经元HOX/FOXP1编程的小鼠的肌肉活动模式和运动行为。 其次，我们将研究运动池身份的丧失如何影响本体感受感官连接的模式。来自脊柱运动神经元的解剖跟踪和生理记录将比较对照和运动神经元特异性FOXP1突变小鼠的感觉对和运动神经元对拮抗剂对之间的单突触连接的特征。同时，我们将确定运动池身份丧失对提供单个肢体肌肉的本体感受感觉神经元子集的分子规范的影响。 第三，我们将研究FOXP1突变体中电动池身份的丧失如何使局部抑制回路组装的选择性消失。生理研究将决定运动神经元特异性FOXP1突变体中IA抑制性神经元与运动神经元的连通性模式如何改变。分子标记将用于识别IA抑制性中间神经元，并检查运动池身份的侵蚀如何影响这组神经元的输出和连通性。 总之，这些研究旨在在运动电路组件的分子程序与这些电路的行为输出之间建立联系。从长远来看，这些见解应有助于设计更有效的策略，以促进创伤性脊髓损伤和运动神经元退化性疾病后脊柱回收的功能恢复。 公共卫生相关性：脊柱运动神经元电路的活性对于运动至关重要，对这些电路的损害 - 通过创伤性损伤或神经退行性疾病 - 是一个主要的财政和社会负担。该提案中概述的研究旨在定义控制脊柱运动回路组织的细胞和分子机制，为治疗脊髓损伤和运动神经元疾病的更多理性方法开辟了道路。