Role of the Atoh1 Lineage in Merkel Cell Development and Maintenance

[摘要] Merkel cells are mechanosensory cells found in mammalian epidermis that are important for the detection of texture, size and shape. These epidermally-derived cells are present in both glabrous and hairy skin, are innervated by slowly adapting type 1 (SA1) afferents, and express the transcription factor Atoh1 from their specification into maturity. In this dissertation I sought to identify and characterize the generation and maintenance of the Atoh1+ Merkel cell lineage using transgenic mice. I found that embryonic Atoh1+ cells are proliferatively capable and unipotent, generating only mature Merkel cells. Contrary to previous estimates, these embryonic-born Merkel cells persist into late adulthood in both hairy and glabrous skin, making them the longest-lived post-mitotic cell present in mammalian epidermis. Despite this, production of Merkel cells in adulthood can be induced by mechanical abrasion caused by repeated skin shaving. Unlike embryonic Merkel cells, these de novo Merkel cells do not arise from Atoh1+ or K14+ progenitors and have a decreased probability of survival compared to original Merkel cells. Furthermore, ectopic Atoh1 expression is sufficient to induce production of ectopic Merkel cells outside the touch dome boundaries. These ectopic Merkel cells express multiple canonical Merkel cell markers and a small percentage that reside in the hair follicle bulge can persist for at least 3 months post-induction. Competency of keratinocytes to respond to Atoh1 varies by skin location, developmental age and hair cycle stage. Also, the Notch signaling pathway plays an instructive role in epidermal cell responsiveness to Atoh1 expression. Together, these experiments provide novel insight into Merkel cell genesis and maintenance as well as illustrate two mechanisms by which Merkel cells production can be initiated in adulthood. They also suggest that the skin cancer, Merkel cell carcinoma, is more likely to arise from epidermal keratinocytes than the Merkel cell lineage.

[发布机构] the University of Pittsburgh

[效力级别] Touch