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（由适用提供）：皮肤体感系统处理有机体“感觉”的信息，例如疼痛，压力，温度和触摸。点，边缘和曲率的检测是由默克尔细胞神经蛋白复合物介导的。这些复合物包括缓慢适应I型（SAI）神经纤维和默克尔细胞，并在无毛（无毛（无毛）皮肤的表皮 - dermal边界，晶须卵泡和专门的毛茸茸的皮肤的区域称为触摸域。皮肤SAI神经神经与默克尔细胞分化无关，并在没有默克尔细胞的情况下保持。然而，SAI传入暴露于缺乏默克尔细胞的小鼠中的典型末端分支和原型SAI电生理反应的丧失。这表明默克尔细胞可能通过当前未定义的机制指导这些神经元的分化/成熟发挥作用。尽管触摸具有至关重要的和基本的性质，但在所有感官中，它是最不理解的。因此，控制体感神经元规范和分化的分子途径已成为激烈研究的重点。转录因子和神经营养蛋白受体（NTRS）的结合指导了背根神经节（DRGS）的体感神经元的分化。另外，神经营养蛋白在体感神经元存活和神经落生中起作用。在SAI传入中控制这些过程的确切机制以及指导它们的NT信号的明确来源是未知的。这对治疗多种人类状况具有影响，在体感觉系统中存在固有的缺陷（自身免疫性疾病，脱髓鞘疾病，遗传异常，感染，损伤，代谢性疾病，毒性暴露和毒性暴露和血管疾病）。该提案的目的旨在检查指示DRG神经元假设SAI纤维表型不同方面的因素。传统上，少量的LTMR，它们在高度异质DRG中的随机分布以及缺乏分子身份的缺乏，已经排除了这种类型的分析。但是，我们的实验室产生了缺乏默克尔细胞的小鼠，为我们提供了研究SAI神经元规范，分化和神经的周围控制的独特机会。该提案的目标是：A。研究默克尔细胞在皮肤发育过程中SAI传入分支中的功能。传入神经准确地靶向缺乏默克尔细胞的触摸域，但它们表现出异常的分支。我们将对K14中的SAI传入分支进行定量分析； ATOH1CKO和野生型动物，以定义分支的改变。这将确定神经元是否无法完成其与SAI神经元的区分，还是成功 在没有默克尔细胞的情况下成熟但无法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ATOH1中的SAI传入分支进行定量分析； BDNFCKO和WildType小鼠定义了默克尔细胞衍生的BDNF是否在传入分支模式中起作用。这些实验将提供一种机制，从而靶向神经教学神经元的形态。 B.研究DRG神经元亚型分化和维持是否需要默克尔细胞。皮肤中默克尔细胞的丧失导致A级种群反应的重新分布。我们将检查默克尔细胞是指导SAI的分化还是维持分化状态所必需的。此外，我们还将在DRG神经元特征中使用依赖性变化，以确定在SAI分化和维持该命运中重要的分子。这些实验将确定与SAI同一性有关的分子级联反应以及对这些过程的外围贡献。