Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

The channel-forming glycoprotein Pannexin 3 (PANX3) functions in cutaneous wound healing and keratinocyte differentiation, but its role in skin homeostasis through aging is not yet understood. We found that PANX3 is absent in newborn skin but becomes upregulated with age. We characterized the skin of global Panx3 knockout mice (KO) and found that KO dorsal skin showed sex-differences at different ages, but generally had reduced dermal and hypodermal areas compared to aged-matched controls. Transcriptomic analysis of KO epidermis revealed reduced E-cadherin stabilization and Wnt signalling compared to WT, consistent with the inability of primary KO keratinocytes to adhere in culture, and diminished epidermal barrier function in KO mice. We also observed increased inflammatory signalling in KO epidermis and higher incidence of dermatitis in aged KO mice compared to wildtype controls. These findings suggest that during skin aging, PANX3 is critical in the maintenance of dorsal skin architecture, keratinocyte cell-cell and cell-matrix adhesion and inflammatory skin responses. Summary Pannexin 3 is a new regulator of skin structure and function. Here, O’Donnell et al. demonstrate its role in the maintenance of proper skin architecture with aging, epidermal barrier function, inflammation, and keratinocyte adhesion through Wnt signalling and E-cadherin stabilization.