Cytoneme-mediated intercellular signaling in keratinocytes essential for epidermal remodeling

Abstract

SummaryThe skin, the body’s largest organ, functions as a primary defense mechanism. Epidermal stem cells supply undifferentiated keratinocytes that differentiate as they migrate toward the outermost skin layer. Although such a replenishment process is disrupted in various human skin diseases, its underlying mechanisms remain elusive. With high-resolution live imaging and in vivo manipulations, we revealed that Notch signaling between keratinocytes is mediated by signaling filopodia called cytonemes and is essential for proper keratinocyte differentiation and proliferation. Inhibiting keratinocyte cytonemes reduces Notch within undifferentiated keratinocytes, leading to abnormal differentiation and hyperproliferation, resembling human skin disease phenotypes. Overproduction of Interleukin (IL)-17 signal, associated with skin diseases likepsoriasis, induces psoriatic phenotypes via cytonemes in zebrafish. Clathrin interactor 1 (clint1), crucial for epidermal homeostasis in zebrafish and humans, regulates cytoneme extension. Our study suggests that intercellular signaling between keratinocytes via cytonemes is critical for epidermal maintenance, and its misregulation could be an origin of human skin diseases.