Oral Presentation Australasian Society for Dermatological Research Annual Scientific Meeting 2017

The Cdon-Shh-Edn1 axis exacerbates naevogenesis in a cell extrinsic manner (#8)

Arash Chitsazan 1 , Graeme Walker 1
  1. QIMR Berghofer Medical Research Institute, BOWEN HILLS, QLD, Australia

Melanocytic neoplasias are classified as benign naevus, melanocytoma (animal type melanoma) and malignant melanoma based on their metastatic potential. Little is known about the genesis and mechanism of formation of these lesions. Here, we utilised Collaborative Cross, a resource of mouse strains designed to discover genes for complex diseases, together with a transgenic mouse bearing Cdk4::Tyr-NRAS mutation. Progeny from 70 Collaborative Cross strains developed a wide spectrum of melanocytic neoplasias based on their innate genetic background. Using quantitative trait locus, fine mapping, loss of function and gene expression studies, and immunohistochemistry analysis, we identified and confirmed Cdon as the causal gene for development of melanocytoma. Mechanistically, this occurs via release of endothelin-1 from keratinocytes expressing high levels of Cdon, which stimulates melanocytes by binding to its receptor, Ednrb. Our study reveals a novel picture whereby innate gene variants that regulate the expression of keratinocyte cytokines drive the formation of melanocytoma.

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