Proper establishment and continuous maintenance of the skin epidermal barrier are critical to protect organisms from pathogens and other external stresses. However, how the adult epidermal barrier is maintained and whether disturbed barrier maintenance causes disease is not known. This study illustrates that epidermal barrier morphogenesis and maintenance are molecularly distinct processes. Further we show that adult barrier repair upon damage recapitulates the morphogenetic program. Mechanistically, the stratum corneum protein and protein-bound lipids direct barrier establishment and repair, whereas the lipid matrix dominates homeostatic maintenance. A switch in epidermal ceramide synthase (CerS) expression characterizes the transition between morphogenetic and homeostatic programs, with CerS3 dominating morphogenesis and CerS4 homeostasis. Consequently, CerS4 controls barrier maintenance but is not required for morphogenesis. Epidermal loss of CerS4 disturbs adult epidermal lipid barrier homeostasis, ultimately resulting in skin inflammation, acanthosis, and hyperkeratosis recapitulating features of human skin disease. These studies highlight the molecular specificity of barrier morphogenesis, maintenance and repair and identify disturbances in epidermal lipid metabolism and barrier homeostasis as underlying causes for inflammatory skin disease in adults.

Epidermal barrier maintenance and morphogenesis are molecularly distinct and ceramide synthase 4 is a novel key player in epidermal barrier maintenance