Molecular mechanisms in controlling development of touch-sensing neurons

控制触觉神经元发育的分子机制

基本信息

批准号：
8658495
负责人：
Wenqin Luo
金额：
$ 34.17万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658495
关键词：
Address Adult Affect Afferent Neurons Alleles Animal Behavior Antigen-Presenting Cells Biological Models Collection Data Development Discrimination Disease ETV1 gene Etiology Future Genes Genetic Programming Genetic Transcription Genets Goals Human In Situ Hybridization Injury Knockout Mice Life Maintenance Mammals Mechanoreceptors Mediating Mitogen-Activated Protein Kinases Modality Molecular Molecular Genetics Mus Mutation Neonatal Nerve Regeneration Neurons Nuclear Organ Pacinian Corpuscles Pathway interactions Pattern Perception Peripheral Phosphorylation Physiological Population Positioning Attribute Property Proprioceptor Proto-Oncogenes RET gene Receptor Protein-Tyrosine Kinases Research Role Schwann Cells Sensory Sex Behavior Signal Pathway Signal Transduction Social Interaction Specific qualifier value Spinal Ganglia Staging Texture Tissues To specify Touch sensation Trigeminal System axon growth axon regeneration axonal pathfinding base human disease improved in vivo insight motor control neural circuit neuron development neuronal survival novel public health relevance research study somatosensory transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Touch sensation, which is essential for our daily life, social interactions and sexual behaviors, is mediated by mechanosensory neurons within the trigeminal (TG) and dorsal root ganglion (DRG). Despite its importance, touch sensation is poorly understood in mammals. The molecular basis of mechanosensitivity, the developmental mechanisms that generate different types of mechanosensory neurons and circuits, and their unique functions, are largely unknown. Our long-term goal is to understand, at the molecular, cellular and circuit levels, the developmental mechanisms and the function of different types of mammalian mechanosensory neurons, using mice as a model system. Previously, we discovered that a small population of mouse somatosensory neurons expressing the neurotrophic receptor tyrosine kinase Ret develops into a classic type of mammalian mechanosensory neuron, the rapidly adapting (RA) mechanoreceptors. Moreover, we established a central role for Ret in controlling the development RA mechanoreceptors and found that peripheral end organs of one subtype of RA mechanoreceptors, the Pacinian corpuscles, are not formed in Ret knock-out mice. However, the signaling targets of Ret to specify different subtypes of RA mechanoreceptors remain elusive. Interestingly, our preliminary studies have identified the ETS transcription factor Er81 as an important target of Ret signaling in the specification of Pacinian corpuscle neurons. We propose to elucidate the roles of a Ret/Er81 signaling pathway in controlling the development of Pacinian corpuscle neurons. Aim I: Characterize the function of Er81 in Pacinian corpuscle and touch circuit formation. We will thoroughly characterize the expression of Er81 in RA mechanoreceptors using in situ hybridization and immunostaining at different developmental stages. We will also address the primary deficits of Er81 null Pacinian corpuscle neurons and use tissue specific knockout mice to determine if Er81 is required not only in neurons but also in accessory cells for Pacinian corpuscle formation. Lastly, we will address whether Er81 is required for maintenance of Pacinian corpuscles by ablating Er81 in adult mice. Aim II: Determine how Ret regulates Er81 to control the development of Pacinian corpuscle neurons. We will examine if Ret signaling is required and/or sufficient for regulating Er81 transcription, phosphorylation and nuclear localization in Pacinian corpuscle neurons. We will also determine if Er81 is necessary and/or sufficient for mediating the Ret signaling. Finally, we will address if Ret regulates Er81 through the mitogen- activated protein kinase (MAPK) pathway. In summary, the proposed research will determine (1) if Er81 is a novel target of Ret signaling to control the development of Pacinian corpuscle neurons and (2) how Ret signaling regulates Er81 in vivo. Results from this research will greatly improve our understanding of how mammalian mechanoreceptors develop and provide insight into axonal regeneration after injuries.

描述（由申请人提供）：触觉对于我们的日常生活、社交互动和性行为至关重要，由三叉神经（TG）和背根神经节（DRG）内的机械感觉神经元介导。尽管触觉很重要，但我们对哺乳动物的触觉知之甚少。机械敏感性的分子基础、产生不同类型机械感觉神经元和回路的发育机制及其独特功能在很大程度上是未知的。我们的长期目标是以小鼠为模型系统，在分子、细胞和电路水平上了解不同类型哺乳动物机械感觉神经元的发育机制和功能。此前，我们发现一小群表达神经营养受体酪氨酸激酶Ret的小鼠体感神经元发育成经典类型的哺乳动物机械感觉神经元，即快速适应（RA）机械感受器。此外，我们确定了 Ret 在控制 RA 机械感受器发育中的核心作用，并发现 RA 机械感受器一种亚型的外周终末器官（Pacinian 小体）在 Ret 敲除小鼠中没有形成。然而，Ret 指定 RA 机械感受器不同亚型的信号传导目标仍然难以捉摸。有趣的是，我们的初步研究已确定 ETS 转录因子 Er81 是 Pacinian 小体神经元规范中 Ret 信号传导的重要靶标。我们建议阐明 Ret/Er81 信号通路在控制 Pacinian 小体神经元发育中的作用。目标 I：表征 Er81 在 Pacinian 小体和触觉电路形成中的功能。我们将利用原位杂交和免疫染色在不同发育阶段彻底表征 RA 机械感受器中 Er81 的表达。我们还将解决 Er81 缺失的 Pacinian 小体神经元的主要缺陷，并使用组织特异性敲除小鼠来确定 Er81 是否不仅在神经元中需要，而且在 Pacinian 小体形成的辅助细胞中也需要。最后，我们将通过消除成年小鼠的 Er81 来探讨 Er81 是否是维持 Pacinian 小体所必需的。目标 II：确定 Ret 如何调节 Er81 来控制 Pacinian 小体神经元的发育。我们将检查 Ret 信号传导是否需要和/或足以调节 Pacinian 小体神经元中的 Er81 转录、磷酸化和核定位。我们还将确定 Er81 对于调解 Ret 信号是否必要和/或充分。最后，我们将讨论 Ret 是否通过丝裂原激活蛋白激酶 (MAPK) 途径调节 Er81。总之，拟议的研究将确定（1）Er81是否是Ret信号传导控制Pacinian小体神经元发育的新靶标，以及（2）Ret信号传导如何在体内调节Er81。这项研究的结果将极大地提高我们对哺乳动物机械感受器如何发育的理解，并为损伤后轴突再生提供见解。