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. Herein, we show 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. Our results establish a role for p73 in cutaneous wound healing through regulation of basal keratinocyte function.
Highlights
The p53 family of transcription factors (p53, p63, and p73) play critical roles in cell cycle regulation, DNA damage response, and cellular differentiation [1,2,3,4,5,6,7,8,9]
In order to validate that the pan-p73 antibody (EP436Y) used in our studies did not cross-react with p63 and confound results, we conducted immunoblot analyses on a diverse p73 regulates epidermal wound healing and induced keratinocyte programming set of primary and transformed human epithelial cells using p73 (EP436Y), p63 (AF1916), and p63α (H-129) antibodies (S1A Fig)
We discovered that p73 is required for timely cutaneous wound healing in mice. p73-/- mice exhibited delayed wound healing, due in part to decreased proliferation and increased activation of the DNA damage response in basal keratinocytes at the epidermal wound edge
Summary
The p53 family of transcription factors (p53, p63, and p73) play critical roles in cell cycle regulation, DNA damage response, and cellular differentiation [1,2,3,4,5,6,7,8,9]. All three family members share structural and functional homology in their transactivation (TA), DNA binding, and oligomerization domains [10]. Due to the high degree of sequence homology in their DNA binding domains, family members bind to similar genomic regions and regulate overlapping target genes. Both p73 and p63 have two distinct promoters that encode for either a longer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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