The Role of p73 in Basal Keratinocyte Function

Abstract

p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. The work presented within this dissertation was carried out with the goal of expanding our knowledge of the biological roles of p73 in basal epithelial cells, the stem cell population of many tissues. The dissertation primarily focuses on the role of p73 in basal keratinocytes of the skin and identifies p73 as a regulator of epidermal wound healing and keratinocyte gene expression. We discovered that p73-deficient mice exhibit delayed wound healing despite morphologically normal-appearing skin. The delay in wound healing is accompanied by decreased proliferation and increased levels of biomarkers of the DNA damage response in basal keratinocytes at the epidermal wound edge. In wild-type mice, this same cell population exhibited increased p73 expression after wounding. Analyzing single-cell transcriptomic data, we found that p73 was expressed by epidermal and hair follicle stem cells, cell types required for wound healing. Moreover, we discovered that p73 isoforms expressed in the skin (ΔNp73) enhance p63-mediated expression of keratinocyte genes during cellular reprogramming from a mesenchymal to basal keratinocyte-like cell. We identified a set of 44 genes directly or indirectly regulated by ΔNp73 that are involved in skin development, cell junctions, cornification, proliferation, and wound healing. In summary, our results establish a role for p73 in epidermal wound healing through regulation of basal keratinocyte function and highlights the importance of studying the functional interplay between p73 and p63.