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: 8452422
• 负责人: ERIN G REED
• 金额: $ 5.39万
• 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/8452422
• 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; 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.

描述（由申请人提供）：皮肤体感系统处理生物体“感觉”的信息，例如疼痛、压力、温度和触觉，由默克尔细胞神经突复合体介导。缓慢适应 I 型 (SAI) 神经纤维和默克尔细胞，存在于手和脚无毛（无毛）皮肤的表皮-真皮边界处，胡须毛囊和被称为触摸圆顶的毛状皮肤的特殊区域的发育独立于默克尔细胞的分化，并且在没有默克尔细胞的情况下得以维持。然而，SAI 传入神经在小鼠中表现出旺盛的末端分支和典型的 SAI 电生理反应的丧失。这表明默克尔细胞可能通过目前未定义的机制在指导这些神经元的分化/成熟中发挥作用，尽管触摸具有关键和基本的性质。因此，控制体感神经元规范和分化的分子途径一直是深入研究的焦点，转录因子和神经营养蛋白受体（NTR）的组合指导着背根体感神经元的分化。此外，神经营养素在体感神经元存活和神经突生长中发挥作用，控制 SAI 传入神经元这些过程的确切机制，以及这些过程的明确来源。指导它们的 NT 信号尚不清楚，这对于治疗许多体感系统存在固有缺陷的人类疾病（自身免疫性疾病、脱髓鞘疾病、遗传异常、感染、损伤、代谢紊乱、有毒物质暴露）具有重要意义。该提案的目的是检查指示 DRG 神经元呈现 SAI 纤维表型不同方面的因素。传统上，LTMR 数量较少，它们在高度范围内随机分布。 DRG 的异质性和分子同一性的缺乏阻碍了这种类型的分析；然而，我们的实验室已经培育出缺乏默克尔细胞的小鼠，为我们提供了研究 SAI 神经元规范、分化和神经支配的外周控制的独特机会。该提案是： A. 研究皮肤发育过程中默克尔细胞在 SAI 传入分支中的功能。传入神经准确地瞄准缺乏默克尔细胞的触觉圆顶，但它们表现出异常分支。 K14 中的 SAI 传入分支；Atoh1CKO 和野生型动物中定义分支如何改变这将决定神经元是否未能完成向 SAI 神经元的分化。 我们还将从 Merkel 细胞中删除 BDNF，并对 Atoh1 和野生型小鼠中的 SAI 传入分支进行定量分析，以确定 Merkel 细胞来源的 BDNF 是否发挥作用。 B. 研究 DRG 神经元亚型分化是否需要 Merkel 细胞。皮肤中默克尔细胞的损失导致 A¿ 的重新分布。我们将检查 Merkel 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，我们将利用 DRG 神经元特征的 Merkel 依赖性变化来识别在 SAI 分化和维持中重要的分子。这些实验将确定参与 SAI 身份的分子级联以及对这些过程的外围贡献。