Molecular mechanisms in controlling development of touch-sensing neurons

控制触觉神经元发育的分子机制

• 批准号: 8556523
• 负责人: Wenqin Luo
• 金额: $ 34.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8556523
• 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

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）：触觉是我们日常生活、社会交往和性行为所必需的，由三叉神经（TG）和背根神经节（DRG）内的机械感觉神经元介导。尽管它的重要性，触觉在哺乳动物中知之甚少。机械敏感性的分子基础，产生不同类型的机械感觉神经元和回路的发育机制，以及它们独特的功能，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。在此之前，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，我们建立了一个中心的作用，Ret在控制RA机械感受器的发展，并发现外周终末器官的一个亚型的RA机械感受器，Pacinian小体，没有形成在Ret基因敲除小鼠。然而，Ret指定不同亚型的RA机械受体的信号转导靶点仍然难以捉摸。有趣的是，我们的初步研究已经确定ETS转录因子Er 81作为一个重要的目标，Ret信号在Pacinian小体神经元的规格。我们建议阐明Ret/Er 81信号通路在控制环层小体神经元发育中的作用。目的一：探讨Er 81在环层小体和触觉回路形成中的作用。我们将彻底表征ER 81在RA机械感受器中的表达，使用原位杂交和免疫染色在不同的发育阶段。我们还将解决的主要缺陷Er 81空Pacinian小体神经元和使用组织特异性基因敲除小鼠，以确定是否Er 81不仅需要在神经元，但也在辅助细胞Pacinian小体的形成。最后，我们将解决是否需要Er 81的维持Pacinian小体消融Er 81在成年小鼠。目的二：研究Ret如何调控Er 81蛋白对环层小体神经元发育的调控作用。我们将检查是否Ret信号是必需的和/或足够的调节Er 81的转录，磷酸化和核定位在Pacinian小体神经元。我们还将确定Er 81对于介导Ret信号传导是否是必要的和/或足够的。最后，我们将讨论Ret是否通过丝裂原活化蛋白激酶（MAPK）途径调节Er 81。 综上所述，本研究将确定（1）Er 81是否是Ret信号转导控制Pacinian小体神经元发育的新靶点，以及（2）Ret信号转导如何在体内调节Er 81。这项研究的结果将大大提高我们对哺乳动物机械感受器如何发育的理解，并为损伤后的轴突再生提供见解。