ΔNp63 controls stemness and inflammation in the adult epidermis

Abstract

The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is poorly understood. Here we show that acute genetic ablation of {Delta}Np63, the main p63 isoform, in adult epidermis disrupts keratinocyte proliferation and self-maintenance and, unexpectedly, triggers an inflammatory psoriasis-like condition. Mechanistically, single-cell RNA sequencing revealed down-regulation of the cell cycle genes, up-regulation of differentiation markers, and induction of several pro-inflammatory pathways in {Delta}Np63-ablated keratinocytes. Intriguingly, {Delta}Np63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This is not associated with active cell death mechanisms, but rather with reduced self-maintenance capacity. Indeed, in vivo wound healing assay, a physiological readout of the epidermal stem cell function, is severely impaired in {Delta}Np63-ablated mice. We found that the Wnt signaling pathway (Wnt10a, Fzd6, Fzd10) and the AP1 factors (JunB, Fos, FosB) are the likely {Delta}Np63 effectors responsible for keratinocyte proliferation/stemness and suppression of differentiation, respectively, while interleukins IL-1a, IL-18, IL-24, and IL-36{gamma} are the likely negative effectors responsible for the suppression of inflammation. These data establish {Delta}Np63 as a critical node that coordinates epidermal homeostasis, stemness, and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways.