Merkel cells specify innervating SAI sensory neuron phenotype.

默克尔细胞指定支配 SAI 感觉神经元的表型。

• 批准号: 8315102
• 负责人: ERIN G REED
• 金额: $ 5.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-06 至 2015-02-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315102
• 关键词: Address; Adolescent; Affect; Afferent Neurons; Animal Model; Animals; Autoimmune Diseases; Biological Models; Brain-Derived Neurotrophic Factor; Cell Differentiation process; Cells; Characteristics; Complex; Cutaneous; Data; Defect; Demyelinating Diseases; Dermal; Detection; Development; Discrimination; Dorsal; Exhibits; Family; Fiber; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic; Goals; Growth Factor; Hand; Human; Immunohistochemistry; Infection; Injury; Laboratories; Ligands; Maintenance; Mechanoreceptors; Mediating; Merkel Cells; Metabolic Diseases; Molecular; Molecular Abnormality; Morphology; Mus; Nature; Nerve Fibers; Nerve Growth Factor Receptors; Neural Crest Cell; Neural tube; Neurites; Neurons; Neurotrophin 3; Organism; Pain; Pathogenesis; Pathway interactions; Pattern; Perception; Peripheral; Phenotype; Play; Population; Positioning Attribute; Process; Research Training; Role; Shapes; Signal Transduction; Skin; Source; Specific qualifier value; Spinal Cord; Spinal Ganglia; Structure; System; Temperature; Texture; Touch sensation; Toxicant exposure; Vascular Diseases; Vibrissae; afferent nerve; design; foot; human disease; information processing; insight; mouse model; nerve supply; neuron development; neuronal survival; neurotrophic factor; novel strategies; postnatal; pressure; receptor; receptor expression; research study; response; somatosensory; transcription factor; transdifferentiation

DESCRIPTION (provided by applicant): The cutaneous somatosensory system processes information that organisms "feel", such as pain, pressure, temperature, and touch. Detection of points, edges, and curvature is mediated by the Merkel cell neurite complex. These complexes consist of slowly adapting type I (SAI) nerve fibers and Merkel cells, and are found at the epidermal-dermal border of glabrous (hairless) skin of the hands and feet, whisker follicles, and specialized regions of hairy skin called touch domes. Cutaneous SAI innervation develops independently of Merkel cell differentiation, and is maintained in the absence of Merkel cells. However, SAI afferents exhibit exuberant terminal branching and loss of prototypical SAI electrophysiological responses in mice that lack Merkel cells. This suggests that Merkel cells may play a role in directing differentiation/maturation of these neurons by currently undefined mechanisms. Despite the critical and fundamental nature of touch, it is the least well understood of all the senses. As such, the molecular pathways that control somatosensory neuron specification and differentiation have been the focus of intense study. A combination of transcription factors and neurotrophin receptors (NTRs) directs the differentiation of somatosensory neurons of the dorsal root ganglia (DRGs). In addition, neurotrophins function in somatosensory neuron survival and neurite outgrowth. The exact mechanisms that govern these processes in SAI afferents, and the explicit sources of the NT signals that direct them, are unknown. This has implications for the treatment of a number of human conditions where there are inherent defects in the somatosensory system (autoimmune diseases, demyelinating diseases, genetic abnormalities, infections, injuries, metabolic disorders, toxic exposures, and vascular disorders). The aims of this proposal are designed to examine the factors that instruct DRG neurons to assume different aspects of the SAI fiber phenotype. Traditionally, the small number of LTMRs, their random distribution within the highly heterogeneous DRG, and the lack of molecular identity have precluded this type of analysis; however, our laboratory has generated mice lacking Merkel cells, providing us with a unique opportunity to study peripheral control of SAI neuron specification, differentiation, and innervation. The goals of this proposal are: A. To investigate the function of Merkel cells in SAI afferent branching during skin development. Afferent nerves accurately target touch domes that lack Merkel cells, but they display aberrant branching. We will perform a quantitative analysis of SAI afferent branching in K14; Atoh1CKO and wild-type animals to define how branching is altered. This will determine whether the neuron fails to complete its differentiation to a SAI neuron or whether it successfully matures but fails to maintain the fully differentiated state in the absence of Merkel cells. We wil also delete BDNF from Merkel cells and perform quantitative analysis of SAI afferent branching in Atoh1; BdnfCKO and wildtype mice to define whether Merkel cell-derived BDNF plays a role in afferent branching patterns. These experiments will provide a mechanism whereby target innervation instructs neuron morphology. B. To investigate whether Merkel cells are required for DRG neuron subtype differentiation and maintenance. Loss of Merkel cells in the skin results in redistribution of the A¿ afferent population response. We will examine whether Merkel cells direct differentiation of the SAI or whether they are required for maintenance of the differentiate state. In addition, we will use Merkel dependent-changes in DRG neuron characteristics to identify molecules important in SAI differentiation and maintenance of that fate. These experiments will determine the molecular cascades involved in SAI identity and the peripheral contribution to these processes. PUBLIC HEALTH RELEVANCE: Many different human conditions affect our ability to sense and respond to the world around us. Treatment of these conditions hinges on understanding their pathogenesis, which can only come from understanding the development and maintenance of the somatosensory system. This project addresses the development of the neurons responsible for relaying information regarding curvature, shape, and texture from the skin to the spinal cord. We expect our studies to elucidate general mechanisms controlling sensory neuron development and function and to provide a structure upon which to understand derangements of neuronal development and survival that occur in human disease.

描述（由申请人提供）：皮肤体感系统处理生物体“感觉”的信息，如疼痛、压力、温度和触觉。点、边缘和曲率的检测由默克尔细胞神经突复合体介导。这些复合体由缓慢适应I型（SAI）神经纤维和默克尔细胞组成，存在于手和脚的无毛（无毛）皮肤的表皮-真皮边界、须毛囊和被称为触摸圆顶的有毛皮肤的专门区域。皮肤SAI神经支配的发展独立于默克尔细胞分化，并在没有默克尔细胞的情况下维持。然而，在缺乏默克尔细胞的小鼠中，SAI传入表现出旺盛的末端分支和原型SAI电生理反应的丧失。这表明默克尔细胞可能通过目前尚不明确的机制在指导这些神经元的分化/成熟中发挥作用。 尽管触觉具有批判性和基本性，但它是所有感官中最不为人所知的。因此，控制体感神经元特化和分化的分子通路一直是深入研究的焦点。转录因子和神经营养因子受体（NTR）的组合指导背根神经节（DRG）的体感神经元的分化。此外，神经营养因子在躯体感觉神经元存活和神经突生长中起作用。在SAI传入中控制这些过程的确切机制，以及指导它们的NT信号的明确来源，都是未知的。这对治疗许多人体疾病具有意义，其中在躯体感觉系统中存在固有缺陷（自身免疫性疾病、脱髓鞘疾病、遗传异常、感染、损伤、代谢紊乱、毒性暴露和血管疾病）。 这个建议的目的是研究的因素，指导DRG神经元承担不同方面的SAI纤维表型。传统上，LTMR的数量少，它们在高度异质性的DRG中的随机分布，以及缺乏分子同一性已经排除了这种类型的分析;然而，我们的实验室已经产生了缺乏默克尔细胞的小鼠，为我们提供了一个独特的机会来研究SAI神经元特化、分化和神经支配的外周控制。本提案的目标是：A。探讨默克尔细胞在皮肤发育过程中对SAI传入支的作用。 传入神经准确地定位于缺乏默克尔细胞的触觉圆顶，但它们显示出异常的分支。 我们将对K14、Atoh 1CKO和野生型动物的SAI传入分支进行定量分析，以确定分支是如何改变的。这将确定神经元是否未能完成向SAI神经元的分化或是否成功 成熟但在没有默克尔细胞的情况下不能维持完全分化的状态。我们还将从默克尔细胞中删除BDNF，并对Atoh 1、BdnfCKO和野生型小鼠的SAI传入分支进行定量分析，以确定默克尔细胞衍生的BDNF是否在传入分支模式中发挥作用。这些实验将提供靶神经支配指导神经元形态的机制。B。探讨默克尔细胞在DRG神经元亚型分化和维持中的作用。皮肤中默克尔细胞的丢失导致A？传入群体反应的重新分布。我们将检查默克尔细胞是否指导SAI的分化，或者它们是否是维持分化状态所必需的。此外，我们将使用默克尔依赖性变化的DRG神经元的特点，以确定分子的重要SAI分化和维护的命运。这些实验将确定参与SAI身份的分子级联和这些过程的外围贡献。 公共卫生相关性：许多不同的人类条件影响我们感知和应对周围世界的能力。这些疾病的治疗取决于对其发病机制的理解，而这只能来自于对躯体感觉系统的发育和维持的理解。该项目致力于神经元的发育，这些神经元负责从皮肤到脊髓传递有关曲率，形状和纹理的信息。我们希望我们的研究能够阐明控制感觉神经元发育和功能的一般机制，并提供一个结构，以了解人类疾病中发生的神经元发育和存活的紊乱。