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The G-protein-coupled receptor, endothelin receptor B (EDNRB), is an important regulator of melanocyte survival and proliferation. It acts by stimulating downstream heterotrimeric G proteins, such as Gα q and Gα 1 . Constitutively active, oncogenic versions of Gα q and Gα 11 drive melanomagenesis, but the role of Ednrb in the context of these mutant G proteins has not been previously examined. In this paper, we used a knock-in mouse allele at the Rosa26 locus to force oncogenic GNAQ Q209L expression in melanocytes in combination with Ednrb gene knockout. The resulting pathological analysis revealed that every aspect of melanomagenesis driven by GNAQ Q209L was inhibited. We conclude that even in the presence of oncogenic Gα q , the Ednrb receptor activates normal Gα q and Gα 11 proteins. This likely promotes tumorigenesis by activating phospholipase C-beta, the immediate effector of Gα q/11 . These findings suggest that it might be possible to target upstream receptors to offset the effects of hyperactive G proteins, recognized as the cause of a growing number of human disorders., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary leptomeningeal melanocytic neoplasms represent a spectrum of rare tumors originating from melanocytes of the leptomeninges, which are the inner two membranes that protect the central nervous system. Like other non-epithelial melanocytic lesions, they bear frequent oncogenic mutations in the heterotrimeric G protein alpha subunits, GNAQ or GNA11. In this study, we used Plp1-creERT to force the expression of oncogenic GNAQ Q209L in the multipotent neural crest cells of the ventro-medial developmental pathway, beginning prior to melanocyte cell differentiation. We found that this produces leptomeningeal melanocytic neoplasms, including cranial melanocytomas, spinal melanocytomas, and spinal melanomas, in addition to blue nevus-like lesions in the dermis. GNAQ Q209L drove different phenotypes depending upon when during embryogenesis (E9.5, E10.5, or E11.5) it was induced by tamoxifen and which Cre driver (Plp1-creERT, Tyr-creERT 2 , or Mitf-cre) was used. Given these differences, we propose that melanocytes go through temporary phases where they become sensitive to the oncogenic effects of GNAQ Q209L . R26-fs-GNAQ Q209L ; Plp1-creERT mice will be useful for defining biomarkers for potentially aggressive leptomeningeal melanocytomas and for developing new therapeutics for advanced disease., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

GNAQ and GNA11 are heterotrimeric G protein alpha subunits, which are mutated in a mutually exclusive pattern in most cases of uveal melanoma, one of the most aggressive cancers. Here we introduce the first transgenic mouse model of uveal melanoma, which develops cancers induced by expression of oncogenic GNAQ(Q209L) under control of the Rosa26 promoter. Disease penetrance is 100% by 3 months of age, with 94% of mice also developing lung tumors. In this model, the Yap protein of the Hippo pathway is activated in the eyes, and blood vessels near the lesions in the head and lungs exhibit melanocytic invasion. While full transcription levels are not necessary for GNAQ(Q209L) to transform mouse melanocytes, we obtained suggestive evidence of a selective advantage for increased GNAQ(Q209L) expression in human tumors. Intriguingly, enforced expression of GNAQ(Q209L) progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQ(Q209) mutations in human epithelial melanomas. The mouse model also exhibited dermal nevi and melanocytic neoplasms of the central nervous system, accompanied by impaired hearing and balance, identifying a novel role for GNAQ in melanocyte-like cells of the inner ear. Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ(Q209L) mutations contribute to both the initiation and metastatic progression of uveal melanoma., (©2015 American Association for Cancer Research.)

Primary leptomeningeal melanocytic neoplasms represent a spectrum of rare tumors originating from melanocytes of the leptomeninges, which are the inner two membranes that protect the central nervous system. Like other non‐epithelial melanocytic lesions, they bear frequent oncogenic mutations in the heterotrimeric G protein alpha subunits, GNAQ or GNA11. In this study, we used Plp1‐creERT to force the expression of oncogenic GNAQQ209L in the multipotent neural crest cells of the ventro‐medial developmental pathway, beginning prior to melanocyte cell differentiation. We found that this produces leptomeningeal melanocytic neoplasms, including cranial melanocytomas, spinal melanocytomas, and spinal melanomas, in addition to blue nevus‐like lesions in the dermis. GNAQQ209L drove different phenotypes depending upon when during embryogenesis (E9.5, E10.5, or E11.5) it was induced by tamoxifen and which Cre driver (Plp1‐creERT, Tyr‐creERT2, or Mitf‐cre) was used. Given these differences, we propose that melanocytes go through temporary phases where they become sensitive to the oncogenic effects of GNAQQ209L. R26‐fs‐GNAQQ209L; Plp1‐creERT mice will be useful for defining biomarkers for potentially aggressive leptomeningeal melanocytomas and for developing new therapeutics for advanced disease. [ABSTRACT FROM AUTHOR]