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Fig. 3

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Publication: Phelps et al., 2022 - MITF deficiency accelerates GNAQ-driven uveal melanoma
All Figures: Figures for Phelps et al., 2022

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Fig. 3

A mosaic expression system determines that CYSLTR2^L129Q, YAP^AA, and PLCβ4^D630Y can drive UM tumorigenesis. Mosaic zebrafish are denoted by X➛Y, where X is the gene introduced, and Y is the recipient genotype; Ctl, control GOI–GFP vector; Q, GNAQ^Q209L; C, CYSLTR2 ^L129Q; Q, GNAQ^Q209L; Y, YAP^AA; PLC, PLCB4^D630Y. Germline zebrafish lines and recipient genotypes are as indicated in Figs. 1 and 2. (A) Representative zebrafish images confirm that introduction of GNAQ^Q209L via the GOI–GFP vector results in GFP⁺ pigment patches and tumors. Asterisks and arrows denote pigment patches corresponding to GFP expression. (B) Kaplan–Meier curves show that mosaic zebrafish with control vector or GNAQ^Q209L introduced into pm+ or pm− recipients all have overall survivals that closely mirror their germline pm+, pm−, Qpm+, and Qpm− equivalents (P = n.s.). As with the germline mutants, Q➛pm+ versus Ctl➛pm+ and Q➛pm− versus Ctl➛pm− were both significantly different (P < 0.001, as determined by log-rank test). (C) Kaplan–Meier curves show the effects of mosaic expression of CYSLTR2^L129Q, YAP^AA, and PLCβ4^D630Y in tp53-mutant zebrafish that are either mitfa^+/+ (Left) or mitfa^−/− (Right). Q➛pm+, Q➛pm−, Ctl➛pm+, and Ctl➛pm− data from B are shown for comparison. Statistical significance is as follows: CYSLTR2, C➛pm+ versus Ctl➛pm+ n.s., C➛pm− versus Ctl➛pm− P < 0.0001, as determined by log-rank test; YAP, Y➛pm+ versus Ctl➛pm+ P < 0.0001, Y➛pm− versus Ctl➛pm− P < 0.0001, as determined by log-rank test; PLCβ4, PLC➛pm+ versus Ctl➛pm+ n.s., PLC➛pm− versus Ctl➛pm− P < 0.0001, as determined by log-rank test. (D) Kaplan–Meier curves show that YAP cooperates with mitfa^−/− in a tp53-WT background. Overall survival of Y➛m+ versus YAP➛m−, significant to P < 0.0001, as determined by log-rank test. (E) Kaplan–Meier curves of Q➛Bpm− versus Bpm− controls, with Q➛pm− from B shown for comparison, show that GNAQ^Q209L is dominant over BRAF^V600E in allowing tumors to form the mitfa^−/− background. Statistical significance of overall survival is P < 0.0001 for Q➛Bpm− versus Bpm− and P = 0.0003 for Q➛Bpm− versus Q➛pm−, as determined by log-rank test.

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