KCTD1/KCTD15-Mediated Repression of AP-2α/AP-2β Is Required for Proper Skin Appendage Development and Epidermal Homeostasis.

The transcriptional regulation of skin appendage morphogenesis during development is poorly understood. We identified a previously unknown critical role of KCTD1/KCTD15 complexes in keratinocytes for the proper formation of skin appendages. Individuals with dominant-negative mutations in KCTD1/KCTD15 have sparse hair and anhidrosis, and mice lacking KCTD1 and KCTD15 in keratinocytes have diminished sweat glands and sebaceous glands as well as progressive hair sparseness. In this study, we show that these phenotypes are a consequence of the lack of the repressor function of KCTD1/KCTD15 complexes on AP-2α and AP-2β transcription factors in keratinocytes. Countering the derepression of AP-2α/AP-2β by heterozygosity for their genes rescues skin appendage defects in mice lacking KCTD1/KCTD15 in keratinocytes. Strikingly, loss of AP-2α and AP-2β in keratinocytes results in similar abnormalities, demonstrating that both an increase and a decrease in AP-2α/AP-2β activity impairs skin appendage development. In addition, we find that KCTD1/KCTD15-mediated repression of AP-2α/AP-2β in keratinocytes maintains epidermal homeostasis in the adult and that a dermatitis caused by deficiency of AP-2α in keratinocytes can be prevented by inactivation of KCTD1/KCTD15 complexes. Collectively, our findings identify a critical role of KCTD1/KCTD15 complexes in regulating skin appendage morphogenesis and epidermal homeostasis by repressing AP-2α/AP-2β transcription factors in keratinocytes.