Summary
The skin, the 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 reduced Notch expression within undifferentiated keratinocytes, leading to abnormal differentiation and hyperproliferation, resembling human skin disease phenotypes. Overproduction of Interleukin (IL)-17 signal, associated with skin diseases like psoriasis, induces psoriatic phenotypes via cytonemes in zebrafish. Our study suggests that intercellular signaling between keratinocytes through cytonemes is critical for epidermal maintenance, and its misregulation could be an origin of human skin diseases.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We added additional supporting data to this manuscript. 1) We included the evidence that shows DLC ligand presence on the cytonemes. 2) we also performed il17a loss-of-function studies.