Molecular correlates of proprioceptor subtype identity

本体感受器亚型身份的分子相关性

• 批准号: 10358584
• 负责人: Joriene De Nooij
• 金额: $ 35.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358584
• 关键词: Adult; Afferent Neurons; Axon; Bioinformatics; Cells; Chemicals; Data; Development; Developmental Process; Devices; Disease; Embryo; Environment; Etiology; Feedback; Genetic; Genetic Transcription; Genetic study; Golgi Tendon Organs; Immunologics; Individual; Induced pluripotent stem cell derived neurons; Knowledge; Label; Ligands; Maintenance; Modality; Modeling; Molecular; Motor; Motor output; Movement; Mus; Muscle; Muscle Spindles; Neonatal; Nociceptors; Organ; Pain; Peripheral; Peripheral Nervous System Diseases; Phenotype; Physiological; Preventive; Process; Proprioception; Proprioceptor; Receptor Signaling; Reporter; Role; Sensory; Sensory Receptors; Shapes; Signal Transduction; Signaling Molecule; Technology; Testing; Therapeutic; Time; Touch sensation; Transcript; Viral; Wild Type Mouse; base; combat; differential expression; early embryonic stage; experimental study; genetic approach; induced pluripotent stem cell; insight; loss of function; mechanical stimulus; molecular dynamics; motor behavior; motor control; nerve supply; neuroprosthesis; programs; receptor; sensory feedback; single-cell RNA sequencing; stem cell model; stem cells; transcriptome; transcriptome sequencing; virus genetics

Sensory modalities such as pain, touch, and proprioception serve a crucial role in conveying information regarding the external and internal environment. Recent years have seen progress in defining the molecular basis of nociceptor and touch receptor subtypes, but proprioceptor subtype diversity remains poorly understood at both a cellular and molecular level. Proprioceptive muscle feedback is critical in the planning and adjustment of motor output and derives from three main proprioceptor subclasses: group Ia and group II muscle spindle (MS) afferents, and group Ib Golgi tendon organ (GTO) afferents. But, without genetic access to the individual proprioceptor subtypes, their specific contributions to the execution of coordinated motor movement remain unknown. Proprioceptive sensory neurons (pSNs) extend axons to their peripheral muscle receptors shortly after they establish a `generic' pSN identity. The prevailing view is that proprioceptor MS/GTO subclass identity is determined at these early embryonic stages through intrinsic genetic programs. However, our recent studies identified several transcripts that are preferentially expressed in subsets of proprioceptors after they innervate their MS and GTO sensory organs. Moreover, for at least one of these transcripts expression appears to depend on the presence of sensory receptors. Thus, while it is possible that these transcripts merely reflect differences in MS/GTO afferent maturation, our findings have begun to question the notion that proprioceptor MS/GTO subtype identity strictly depends on intrinsic transcriptional programs. Instead, we hypothesize that i) proprioceptor subclass identity is acquired though a protracted process with a gradual induction and/or selective maintenance of subclass specific transcripts, and ii) is in part induced by retrograde signals from their peripheral sensory organs. This proposal test these ideas through three sets of experiments. First, we will combine viral and genetic strategies to assign a MS (group Ia/II) or GTO (group Ib) subclass identity to a selected set of candidate proprioceptor subtype markers, and test the requirement of these molecules in proprioceptor subtype acquisition. Second, we will take advantage of single cell transcriptome sequencing technologies to delineate the molecular dynamics through which pSN MS/GTO subclass identities emerge during development. Third, we will assess the role of extrinsic signaling molecules in directing pSN subclass identity. Together these studies will provide a comprehensive understanding of the molecular basis of proprioceptor subclass identity, thus permitting renewed efforts to delineate the role of these important sensory neurons in motor control at both a physiological and circuit level.

诸如疼痛、触觉和本体感觉等感觉方式在传递信息方面起着至关重要的作用 外部和内部环境。近年来，在定义分子 伤害感受器和触觉感受器亚型的基础，但本体感受器亚型的多样性仍然很差 在细胞和分子水平上都能理解。本体感觉肌肉反馈在计划中至关重要， 调节运动输出，并来自三个主要的本体感受器亚类：Ia组和II组 肌梭（MS）传入和Ib组高尔基体腱器官（GTO）传入。但是，如果没有基因的进入， 个体本体感受器亚型，它们对协调运动的执行的具体贡献 移动仍然未知。 本体感觉神经元（pSN）在刺激后不久将轴突延伸到它们的外周肌肉受体。 它们建立一个“通用”pSN身份。流行的观点是本体感受器MS/GTO亚类身份是 在这些早期胚胎阶段通过内在的遗传程序决定。然而，我们最近的研究 确定了几种转录本，它们在受神经支配后优先在本体感受器亚群中表达。 他们的MS和GTO感觉器官。此外，对于这些转录本中的至少一种，表达似乎是 取决于感觉受体的存在。因此，虽然这些记录可能仅仅反映了 MS/GTO传入成熟的差异，我们的研究结果已经开始质疑本体感受器 MS/GTO亚型身份严格依赖于内在的转录程序。相反，我们假设i） 本体感受器亚类身份是通过具有逐渐诱导和/或 亚类特异性转录物的选择性维持，和ii）部分由它们的逆行信号诱导， 外周感觉器官 本提案通过三组实验来检验这些想法。首先，我们将联合收割机病毒和 将MS（Ia/II组）或GTO（Ib组）亚类身份分配给选定的一组 候选本体感受器亚型标记物，并测试本体感受器中这些分子的需求 子类型获取。其次，我们将利用单细胞转录组测序技术， 描述了pSN MS/GTO亚类身份出现的分子动力学 发展第三，我们将评估外源性信号分子在指导pSN亚类身份中的作用。 总之，这些研究将提供一个全面的了解的分子基础， 本体感受器亚类的身份，从而允许重新努力描绘这些重要的感觉的作用， 神经元在生理和电路水平上的运动控制。