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

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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.