Summary:
The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is barely investigated. Here we show that acute genetic ablation of ÎNp63, the main p63 isoform, in the 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 ÎNp63-ablated keratinocytes. Intriguingly, ÎNp63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This was not associated with active cell death mechanisms, but rather with reduced stemness and self-maintenance capacity. Indeed, in vivo wound healing assay, a physiological readout of the epidermal stem cell function, was largely impaired in the ablated skin. We found that the Wnt signaling pathway (Wnt5a, Wnt10a, Fzd6, Fzd10) and Col17a1 are the likely ÎNp63 effectors responsible for keratinocyte proliferation and stemness, while AP1 factors are responsible for excessive differentiation, and Il-1a, Il-18, Il-24 and Il-36Î3 for the suppression of inflammation. These data implicate ÎNp63 as a critical node that coordinates balanced epidermal homeostasis and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways.
