Abstract
The epidermis is the first line of defense against ultraviolet (UV) light from the sun. Keratinocytes and melanocytes respond to UV exposure by eliciting a tanning response dependent in part on paracrine signaling, but how keratinocyte:melanocyte communication is regulated during this response remains understudied. Here, we uncover a surprising new function for the keratinocyte-specific cell–cell adhesion molecule desmoglein 1 (Dsg1) in regulating keratinocyte:melanocyte paracrine signaling to promote the tanning response in the absence of UV exposure. Melanocytes within Dsg1-silenced human skin equivalents exhibited increased pigmentation and altered dendrite morphology, phenotypes which were confirmed in 2D culture using conditioned media from Dsg1-silenced keratinocytes. Dsg1-silenced keratinocytes increased melanocyte-stimulating hormone precursor (Pomc) and cytokine mRNA. Melanocytes cultured in media conditioned by Dsg1-silenced keratinocytes increased Mitf and Tyrp1 mRNA, TYRP1 protein, and melanin production and secretion. Melanocytes in Dsg1-silenced skin equivalents mislocalized suprabasally, reminiscent of early melanoma pagetoid behavior. Together with our previous report that UV reduces Dsg1 expression, these data support a role for Dsg1 in controlling keratinocyte:melanocyte paracrine communication and raise the possibility that a Dsg1-deficient niche contributes to pagetoid behavior, such as occurs in early melanoma development.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 305-317 |
| Number of pages | 13 |
| Journal | Pigment Cell and Melanoma Research |
| Volume | 33 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 1 2020 |
Funding
This work was supported by NIH/NIAMS R01 AR041836 and NIH/NCI R01 CA122151 to KJG and by the Liz and Eric Lefkofsky Family Foundation Innovation Research Award to KJG and JLJ. Additional support was provided by the JL Mayberry endowment to KJG. CRA and QRR‐C were supported through a NIH/NCI Ruth L. Kirschstein Training Grant through Northwestern University's Robert H. Lurie Comprehensive Cancer Center (T32 CA070085) “Signal Transduction in Cancer.” CRA was also supported through a NIH/NCI Ruth L. Kirschstein National Research Service Award 1F32CA210498‐01. HEB was supported through a NIH/NCI Ruth L. Kirschstein Training Grant through Northwestern University's Robert H. Lurie Comprehensive Cancer Center (T32 CA080621‐14) “Oncogenesis and Developmental Biology”. JAB was supported by NIH/NIAMS K01 AR075087. We thank Dr. Zalfa Abdel‐Malek (University of Cincinnati) for critical reading of the manuscript. We acknowledge support and materials from the Northwestern University Skin Disease Research Center supported by 5P30AR057216. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was presented in part in October 2018 at the joint Montagna Symposium on the Biology of Skin/Pan American Society for Pigment Cell Research Meeting. Funding for this conference was in part through R13AR009431‐53 and R13AR07429‐01 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and co‐funding was provided by the National Institute on Aging (NIA) and the National Institute of Environmental Sciences (NIEHS). This work was supported by NIH/NIAMS R01 AR041836 and NIH/NCI R01 CA122151 to KJG and by the Liz and Eric Lefkofsky Family Foundation Innovation Research Award to KJG and JLJ. Additional support was provided by the JL Mayberry endowment to KJG. CRA and QRR-C were supported through a NIH/NCI Ruth L. Kirschstein Training Grant through Northwestern University's Robert H. Lurie Comprehensive Cancer Center (T32 CA070085) ?Signal Transduction in Cancer.? CRA was also supported through a NIH/NCI Ruth L. Kirschstein National Research Service Award 1F32CA210498-01. HEB was supported through a NIH/NCI Ruth L. Kirschstein Training Grant through Northwestern University's Robert H. Lurie Comprehensive Cancer Center (T32 CA080621-14) ?Oncogenesis and Developmental Biology?. JAB was supported by NIH/NIAMS K01 AR075087. We thank Dr. Zalfa Abdel-Malek (University of Cincinnati) for critical reading of the manuscript. We acknowledge support and materials from the Northwestern University Skin Disease Research Center supported by 5P30AR057216. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was presented in part in October 2018 at the joint Montagna Symposium on the Biology of Skin/Pan American Society for Pigment Cell Research Meeting. Funding for this conference was in part through R13AR009431-53 and R13AR07429-01 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and co-funding was provided by the National Institute on Aging (NIA) and the National Institute of Environmental Sciences (NIEHS).
Keywords
- desmosomes
- environment
- keratinocytes
- melanocytes
- melanoma
- skin
- sunlight
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
- Dermatology
- Oncology
