Ocular melanocytes respond to oncogenic GNAQQ209L differently compared to epidermal and dermal melanocytes in mice

• Main Author: Huang, Jenny Li-Ying
• Language: English
• Published: University of British Columbia 2015
• Online Access: http://hdl.handle.net/2429/51763

Somatic mutations in the homologous human oncogenes GNAQ, and GNA11, are frequently found in ocular melanomas of the uvea, blue nevi of the dermis, and melanocytic neoplasias of the central nervous system (CNS), but rarely in cutaneous melanoma located in the epidermis (0.3%). The most common mutation found in GNAQ/11 is the amino acid substitution Q209L in the Ras-like GTPase domain. It causes complete or partial loss of intrinsic GTPase activity thereby locking the protein in a constitutively active form. To compare the downstream signal transduction effects of GNAQQ²⁰⁹L on melanocytes in different locations such as the dermis, the epidermis, ears, eyes and CNS, the mutant gene was conditionally knocked-in to the ubiquitous Rosa26 locus in mice to normalize gene expression among melanocytes. When expression of GNAQQ²⁰⁹L was induced in melanoblasts (immature melanocytes) during embryogenesis, the mice exhibit hyperpigmentation in the dermis of the tail, footpad, trunk, and ears beginning at a young age, with non-cutaneous melanocyte overgrowth in the inner ear and CNS, and metastatic uveal melanoma in older animals. In older adult mice, a progressive loss of melanocytes occurred in the inter-follicular epidermis, which could explain the lack of GNAQ mutations in human cutaneous melanomas located in the epidermis. When expression of GNAQQ²⁰⁹L was induced in mature melanocytes in adult, some of the above phenotypes such as hyperpigmentation in the dermal skin and uveal track thickening in the eyes were observed. When expression of GNAQQ²⁰⁹L was induced in bipotential Schwann cell precursors, there was a decrease in the number of melanoblasts, suggesting that GNAQQ²⁰⁹L blocks the production of melanoblasts from Schwann cell precursors. Altogether, I developed the first mouse uveal melanoma model driven by oncogenic mutant GNAQQ²⁰⁹L gene. These mice display all three types of lesions driven by constitutively active GNAQ in human: blue nevi, uveal melanoma, and invasive melanocytic neoplasias of the CNS. I show that the downstream effects of GNAQQ²⁰⁹L on melanocytes are strongly dependent upon cellular context, as seen in the differences presented in the epidermis, dermis, uveal and CNS melanocytes. === Medicine, Faculty of === Medical Genetics, Department of === Graduate