AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis

Abstract

AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2 is the predominant AP-2 family member in adult epidermis, followed by AP-2{beta}. Through inactivation of AP-2, AP-2{beta}, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2{beta} in keratinocytes is compensated for by AP-2, (2) loss of AP-2 impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2/AP-2{beta} results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2/AP-2{beta} in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2 or AP-2/AP-2{beta} in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2/AP-2{beta} are critical regulators of epidermal homeostasis in the adult skin.