CtBP1 Overexpression in Keratinocytes Perturbs Skin Homeostasis

Abstract

Carboxyl-terminal binding protein-1 (CtBP1) is a transcriptional co-repressor with multiple in vitro targets, but its in vivo functions are largely unknown. We generated keratinocyte-specific CtBP1 transgenic mice with a keratin 5 promoter (K5.CtBP1) to probe the pathological roles of CtBP1. At transgene expression levels comparable with endogenous CtBP1 in acute skin wounds, K5.CtBP1 epidermis displayed hyperproliferation, loss of E-cadherin, and failed terminal differentiation. Known CtBP1 target genes associated with these processes, e.g., p21, Brca1, and E-cadherin were down-regulated in K5.CtBP1 skin. Surprisingly, K5.CtBP1 pups also exhibited a hair loss phenotype. We found that expression of the Distal-less 3 (Dlx3), a critical regulator of hair follicle differentiation and cycling, was decreased in K5.CtBP1 mice. Molecular studies revealed that CtBP1 directly suppressed Dlx3 transcription. Consistently, K5.CtBP1 mice displayed abnormal hair follicles with decreased expression of Dlx3 downstream targets Gata3, Hoxc13, and hair keratins. In sum, this first CtBP1 transgenic model provides in vivo evidence for certain CtBP1 functions predicted from in vitro studies, reveals to our knowledge previously unreported functions and transcriptional activities of CtBP1 in the context of epithelial-mesenchymal interplay, and suggest CtBP1 has a pathogenesis role in hair follicle morphogenesis and differentiation.