Neurotrophin 3 and regulation of proprioceptor subtype identity and connectivity

神经营养素 3 与本体感受器亚型身份和连接性的调节

• 批准号: 8934213
• 负责人: Thomas M. Jessell
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934213
• 关键词: Adopted; Agreement; Ankle; Biomechanics; Bypass; Cessation of life; Dependence; Dependency; Development; Embryo; Exhibits; Feedback; Health; Interneurons; Knee; Lead; Limb structure; Link; Mediating; Methods; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Motor output; Muscle; Musculoskeletal; Musculoskeletal Equilibrium; Neurons; Neurotrophin 3; Output; Pathway interactions; Pattern; Peripheral; Population; Proprioceptor; Protocols documentation; Rabies virus; Recombinants; Recruitment Activity; Regulation; Relative (related person); Rest; Role; Sensory; Sensory Receptors; Signal Pathway; Signal Transduction; Spinal; Spinal Cord; Spinal Muscular Atrophy; Spinal cord injury; System; Testing; Time; Transcript; Variant; base; design; differential expression; expectation; first grade; insight; interest; locomotor control; molecular marker; motor disorder; neuron loss; neurotrophic factor; research study; response; therapeutic development; tool; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Proprioceptive sensory neurons (pSNs) serve a key role in refining the output of the spinal motor system through the provision of feedback signals that convey the state of muscle activity to central and spinal motor neurons. Distinct pSN subtypes engage with select spinal circuits dedicated to specific musculoskeletal tasks (e.g. postural control, knee flexion, ankle extension etc). This precision in sensory-motor connectivity is presumed to rest in large part on the molecular distinctions between the various proprioceptor subtypes, yet surprisingly little is known of the way in which proprioceptor subtype identity is established. Challenging prevailing views, our recent studies suggest that certain aspects pSN subtype character are mediated by graded signaling by neurotrophin 3 (NT3) rather than by intrinsic transcriptional determinants. This idea is founded on several observations, most notably the finding that embryonic muscles exhibit muscle- by-muscle differences in NT3 expression levels at the time when pSNs establish their subtype identity. The hypothesis that variations in the strength of NT3 signaling direct pSN subtype character leads to two predictions. First, if graded NT3 signaling drives pSN subtype diversity, NT3 should elicit distinct molecular responses in pSNs that innervate muscle targets expressing different levels of NT3. Second, based on the notion that pSN identity is inherently linked to spinal connectivity patterns, changes in NT3 signaling levels should result in alterations in pSN connectivity patterns. The experiments in the proposal are designed to test these expectations. In agreement with our predictions, in preliminary studies, we identified several molecular markers that are differentiall expressed between pSN subsets that innervate NT3high -and those that innervate NT3low muscle targets. These molecular markers not only provide new insights into the various aspects of pSN subtype identity, but importantly, are powerful tools through which to assess the role of NT3 in regulating pSN diversity (Aim 1). In addition (Aim 2), we will take advantage of newly developed strategies - based on anterograde transsynaptic transfer of recombinant rabies virus - to construct an anatomical framework of the spinal connectivity patterns of defined NT3low and NT3high pSN subsets, and examine the role of NT3 signaling in establishing these patterns. Ultimately, these analysis' should lead to new insights in cardinal molecular and network features of pSN subtypes and may begin to reveal the organizational rules that underlie the formation of spinal sensory- motor circuits.

描述（由申请人提供）：通过提供反馈信号，将肌肉活动状态传达给中枢和脊柱运动神经元，在完善脊柱运动系统的输出方面起着关键作用。不同的PSN亚型与专门针对特定肌肉骨骼任务的精选脊柱回路（例如姿势控制，膝盖屈曲，脚踝伸展等）。人们认为，感觉运动连通性的这种精度很大程度上依赖于各种前粘液器亚型之间的分子区别，但令人惊讶的是，人们对建立了前校感受器亚型身份的方式知之甚少。 我们最近的研究具有挑战性的普遍观点，表明，神经营养蛋白3（NT3）的分级信号传导介导了某些方面，而不是通过固有的转录决定因素介导。这个想法建立在几个观察结果上，最值得注意的是，当PSN建立其亚型身份时，胚胎肌肉在NT3表达水平上表现出肌肉 - 肌肉差异。 NT3信号传导直接PSN亚型特征的强度变化的假设导致了两个预测。首先，如果分级的NT3信号传导驱动PSN亚型多样性，则NT3应在PSN中引起明显的分子反应，从而支配表达不同水平的NT3的肌肉靶标。其次，基于PSN身份与脊柱连接模式固有链接的概念，NT3信号传导水平的变化应导致PSN连接模式的改变。该提案中的实验旨在测试这些期望。 在我们的预测中，在初步研究中，我们确定了几个分子标记物，这些标记是在支配NT3High的PSN亚群之间表达的差异，以及那些支配NT3LOW肌肉靶标的分子标记。这些分子标记不仅为PSN子类型身份的各个方面提供了新的见解，而且重要的是，重要的是评估NT3在调节PSN多样性中的作用的强大工具（AIM 1）。此外（AIM 2），我们将利用新开发的策略 - 基于重组狂犬病病毒的行顺序转移 - 构建定义NT3LOW和NT3HIGH PSN SUBSET的脊柱连接模式的解剖框架，并检查NT3信号在建立这些模式中的作用。 最终，这些分析应该导致对PSN亚型的主要分子和网络特征的新见解，并可能开始揭示脊柱感觉电路形成的组织规则。