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

描述(申请人提供)：触觉障碍是许多影响皮肤和/或周围神经系统的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的部分或全部触觉感受器。Merkel细胞/轴突复合体是皮肤触摸感受器的一种形式，它们由感觉神经纤维和称为Merkel细胞的皮肤细胞组成。默克尔细胞/轴突复合体被认为对两点触摸辨别以及对曲率、形状和纹理的感知非常重要。Atoh1是默克尔细胞表达的一种基本的螺旋-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/轴突复合体检测到的触摸刺激是必不可少的。控制Merkel细胞/轴突复合体的发生和组装的发育过程，Merkel细胞对Atoh1的持续需求，以及这些细胞在人类周围神经系统和皮肤疾病(包括Merkel细胞癌)中所起的作用(S)仍不清楚。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。这项建议的具体目的是：1)确定Merkel细胞缺失对小鼠行为的影响；2)确定Atoh1是否足以指导Merkel细胞的产生；3)确定成年动物Atoh1的条件性丧失如何影响Merkel细胞和Merkel细胞/轴突复合体。我们将使用条件性基因敲除系统从发育中的小鼠皮肤中删除Atoh1，然后使用专门的行为测试来评估由Merkel细胞/神经突起复合体介导的感觉功能。我们还将使用组织学技术来确定Atoh1缺失对成年Merkel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Merkel细胞/轴突复合体的能力。最后，我们将在成人皮肤的不同区域异位表达Atoh1，以确定该基因是否足以指导新的Merkel细胞和/或Merkel细胞癌的产生。 与公共健康相关：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，默克尔细胞是皮肤中的专门细胞，对检测曲率、形状和质地非常重要。人们希望，这些信息将为人们提供一些影响触觉的人类疾病的洞察力。

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.