Epithelia-derived MPZL3 regulates murine epidermal differentiation and sebaceous gland development

Summary: Abstract Body: Previous in vitro and ex vivo studies have shown that Myelin Protein Zero-like 3 (MPZL3) is an essential regulator of human epidermal differentiation. MPZL3 also likely regulates epidermal differentiation in vivo, as Mpzl3 global knockout (GKO) mice show barrier defects and an inflammatory skin phenotype. However, since MPZL3 is expressed in various tissues, extracutaneous changes may have contributed to the skin phenotype. In this study, we investigated the role of epithelia-derived MPZL3 signaling in vivo, using Keratin 14 promoter-driven Cre (epiKO). At E17.5, epiKO embryos showed increased toluidine blue dye permeability, suggestive of delayed barrier formation. Although epiKO pups were indistinguishable from control littermates at birth, they showed perturbed epidermal differentiation (increased filaggrin, Sprr4, Lcn2, S100a9 and Cers4 expression) within 2 weeks and subsequent skin inflammation. Flow cytometry detected increased IL-17+ γδ T cells in the lesional skin. The epiKO pups also showed a significant increase in sebaceous gland size and sebum production (by Oil Red O staining), and bulk RNAseq and qPCR analysis detected up-regulation of genes involved in sebocyte differentiation and lipid metabolism (Keratin 79, epigen, Awat, FASN, perilipin 2, etc.). These results demonstrate that MPZL3 is a key regulator of epidermal barrier formation and sebaceous gland development in vivo, and barrier defects upon epithelia-specific MPZL3 deletion trigger γδ T cell activation and skin inflammation. Given the functional conservation between murine and human MPZL3, MPZL3 signaling may be targeted therapeutically to restore epidermal barrier function or to treat sebum production disorders. Nicole I. Haberland¹, Deborah R. Brooks¹, Alexander J. Hu¹, Sujad Younis³, Natasa Strbo³, Rivka Stone¹, Ralf Paus^{1, 4}, Tongyu C. Wikramanayake^{1, 2} 1. Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, United States. 2. Molecular Cell and Developmental Biology Program, University of Miami Miller School of Medicine, Miami, FL, United States. 3. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States. 4. CUTANEON – Skin & Hair Innovations, Berlin, Germany. Epidermal Structure and Barrier Function