The role of Atoh1 in the development and function of Merkel cells

描述（由申请人提供）：触觉的破坏是影响皮肤和/或外周神经系统的许多遗传性和获得性人类疾病所固有的。这些疾病会影响皮肤中发现的部分或全部触觉感受器。默克尔细胞/神经突复合体是皮肤触觉感受器的一种形式，它们由感觉神经纤维和称为默克尔细胞的皮肤细胞组成。默克尔细胞/神经突复合体被认为是重要的两点触摸歧视和感知的曲率，形状和纹理。Atoh 1是一种由默克尔细胞表达的碱性螺旋-环-螺旋转录因子，是其产生所必需的。反过来，默克尔细胞对于检测由默克尔细胞/神经突复合体检测到的触摸刺激是必不可少的。控制默克尔细胞/神经突复合体的发生和组装的发育过程、默克尔细胞中Atoh 1的持续需求以及这些细胞在人类外周神经系统和皮肤疾病（包括默克尔细胞癌）中发挥的作用仍然未知。我们的目标是了解默克尔细胞如何在感官知觉中发挥作用，并确定控制默克尔细胞发育的遗传因素。本提案的具体目的是：1）确定默克尔细胞缺失对小鼠行为的影响; 2）确定Atoh 1是否足以指导默克尔细胞的产生; 3）确定成年动物中Atoh 1的条件性缺失如何影响默克尔细胞和默克尔细胞/神经突复合体。我们将使用条件性敲除系统从发育小鼠的皮肤中删除Atoh 1，然后使用专门的行为测试来评估由默克尔细胞/神经突复合体介导的感觉功能。我们还将使用组织学技术来确定Atoh 1缺失对成人默克尔细胞的影响，以及这种缺失如何影响受损神经再生和准确靶向默克尔细胞/神经突复合体的能力。最后，我们将在成人皮肤的不同区域异位表达Atoh 1，以确定该基因是否足以指导新的默克尔细胞和/或默克尔细胞癌的产生。 公共卫生相关性：许多神经系统和皮肤疾病会干扰触觉。这项提议将研究默克尔细胞的功能和发育，这种细胞是皮肤中的专门细胞，对检测曲率、形状和纹理很重要。希望这些信息将提供对一些影响触觉的人类疾病的深入了解。

DESCRIPTION (provided by applicant): Disruptions of the sense of touch are inherent to many inherited and acquired human disorders that affect the skin and/or peripheral nervous system. These disorders can affect some or all of the touch receptors that are found in the skin. Merkel cell/neurite complexes are one form of cutaneous touch receptor, and they are composed of sensory nerve fibers and skin cells called Merkel cells. Merkel cell/neurite complexes are thought to be important for two-point touch discrimination and the perception of curvature, shapes and textures. Atoh1 is a basic helix-loop-helix transcription factor expressed by Merkel cells that is necessary for their production. In turn, Merkel cells are essential for the detection of touch stimuli detected by Merkel cell/neurite complexes. The developmental processes that control the genesis and assembly of Merkel cell/neurite complexes, the ongoing requirement for Atoh1 in Merkel cells, and the role(s) that these cells play in human diseases of the peripheral nervous system and skin, including Merkel cell carcinoma, remain unknown. Our goals are to understand how Merkel cells function in sensory perception and to identify the genetic factors that control Merkel cell development. The specific aims of this proposal are to 1) determine the consequences of Merkel cell deletion on mouse behavior; 2) determine whether Atoh1 is sufficient to direct the production of Merkel cells; and to 3) determine how conditional loss of Atoh1 in adult animals affects Merkel cells and Merkel cell/neurite complexes. We will use conditional knockout systems to delete Atoh1 from the skin of developing mice and then use specialized behavioral tests to assess the sensory functions proposed to be mediated by Merkel cell/neurite complexes. We will also use histological techniques to determine the affects of Atoh1 deletion on adult Merkel cells and how this deletion impacts the ability of damaged nerves to regenerate and accurately target Merkel cell/neurite complexes. Finally, we will ectopically express Atoh1 in different regions of adult skin to determine whether the gene is sufficient to direct the creation of new Merkel cells and/or Merkel cell carcinomas. PUBLIC HEALTH RELEVANCE: Many diseases of the nervous system and skin interfere with the sense of touch. This proposal will study the function and development of Merkel cells, specialized cells in the skin that are important for detecting curvature, shape and texture. It is hoped that this information will provide insight into a number of human diseases that affect touch sensation.