Molecular Correlates of Proprioceptor Subtype Identity

本体感受器亚型身份的分子相关性

• 批准号: 10576267
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576267
• 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; Knowledge; Label; Ligands; Maintenance; Modality; Modeling; Molecular; Motor; Motor output; Movement; Mus; Muscle; Muscle Spindles; Neonatal; Neurons; 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; Specific qualifier value; Technology; Testing; Therapeutic; Time; Touch sensation; Transcript; Viral; Wild Type Mouse; combat; differential expression; early embryonic stage; experimental study; gain of function; genetic approach; induced pluripotent stem cell; insight; loss of function; mechanical stimulus; molecular dynamics; motor behavior; motor control; nerve stem cell; nerve supply; neuroprosthesis; programs; receptor; sensory feedback; single-cell RNA sequencing; stem cell model; transcriptome; transcriptome sequencing

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.

感觉方式，如疼痛、触摸和本体感觉，在传递信息中起着至关重要的作用 关于外部和内部环境。近年来，在定义分子的方面取得了进展 伤害性感受器和触摸感受器亚型的基础，但本体感受器亚型多样性较差 在细胞和分子水平上都能被理解。本体感觉肌肉反馈在计划和 运动输出的调节，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高尔基肌腱器官(GTO)传入。但是，如果没有遗传途径 对于个体本体感受器亚型，其对协调运动执行的具体贡献 目前还不知道有什么动向。 本体感觉神经元(PSN)将轴突延伸至其周围肌肉感受器 他们建立了一个“通用的”PSN身份。主流观点认为，本体感受器MS/GTO子类身份是 在这些早期胚胎阶段通过内在遗传程序决定的。然而，我们最近的研究 确定了几个在本体感受器亚群中优先表达的转录本，这些转录本在支配它们之后 他们的MS和GTO感觉器官。此外，至少有一个转录本的表达似乎 取决于感官受体的存在。因此，尽管这些文字记录可能只是反映了 MS/GTO传入成熟的差异，我们的发现已经开始质疑本体感受器的概念 MS/GTO亚型的同一性严格依赖于内在的转录程序。相反，我们假设i) 本体感受器亚类同一性是通过一个漫长的过程逐步归纳和/或获得的 亚类特异转录本的选择性维持，以及ii)部分是由来自其逆行信号诱导的 周围感觉器官。 这项提议通过三组实验来检验这些想法。首先，我们将把病毒和 将MS(Ia/II组)或GTO(Ib组)亚类身份分配给选定的一组 选择本体感受器亚型标记，并测试这些分子在本体感受器中的要求 亚型获取。第二，我们将利用单细胞转录组测序技术来 描绘了PSN MS/GTO亚类身份出现的分子动力学 发展。第三，我们将评估外在信号分子在引导PSN亚类识别中的作用。 这些研究将提供一个全面的分子基础的理解 本体感受器亚类身份，从而允许重新努力来描绘这些重要感觉的作用 神经元在生理和电路水平上都控制着运动。