NIH Reporter #1ZIAAR041221-04

Development and regulation of stem cell lineages in skin

This award supports research on the development and regulation of stem cell lineages in skin, focusing on hair follicle stem cells and Merkel cells. The project investigates the signaling pathways and transcriptional networks involved in Merkel cell formation and differentiation, using advanced sequencing techniques and in vitro models. Findings include novel mechanisms of gene expression regulation relevant to normal skin biology and Merkel cell carcinoma.

Description

Following up on prior work that identified the perineural microenvironment as a regulator of hair follicle stem cells, we have completed a project describing a perivascular niche for hair follicle stem cells. Moreover, we have identified that sensory touch domes in the skin, and the Merkel cells housed there are also regulated by associated Shh signaling from sensory neurons. We have continued experiments demonstrating that touch domes are a novel and distinct cell lineage within the skin maintained by their own stem cell population. We have also investigated the developmental requirements for Merkel cell formation in skin. We have found that establishing the Merkel cell touch dome lineage in embryonic skin requires a cascade of Wnt, Eda, and intraepithelial Shh signaling. We have identified multiple transcriptional networks that are responsible for formation or maintenance of Merkel cells in mouse skin. Ongoing work uses single cell RNA-seq and ATAC-seq to investigate the transcriptional requirements for Merkel cell differentiation. We are applying our understanding of Merkel cell development to generate an in vitro differentiation model of Merkel cell formation. Our studies have identified neuroendocrine lineage factors that are important for both normal Merkel cell formation and are critical in Merkel cell carcinoma. We have also discovered that Merkel cell differentiation is accompanied by the emergence of non-coding transcripts including retained intron transcripts. These retained intron transcripts can form nuclear phase condensates that retain their cognate mRNA transcripts in the nucleus and lower protein levels, representing a novel mechanism to regulate gene expression.

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