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. 2016 Aug 22;126(9):3613–3625. doi: 10.1172/JCI86841

Figure 7. Treatment with pan-PI3K inhibitors improves the mtm zebrafish phenotype.

Figure 7

(A) Severity of fin fold phenotype in 4-dpf mtm mutants is significantly improved after treatment with 5 μM LY294002, 50 nM wortmannin, or 250 nM PI-103 (***P < 0.001), but not by inhibition of class III PI3K with 500 nM VPS34-IN1 (P = 0.4955) or class I PI3Ks with 500 nM GDC-0941 (P = 0.3494). From left to right: n = 92, 110, 108, 97, 92, 94; Kruskal-Wallis test, followed by Dunn’s post-test. (B) At 7 dpf, the mean distance traveled in a 30-second optovin-induced photoactivation period by mtm larvae treated with DMSO alone is 57% that of WT siblings (P < 0.001). Class I inhibition with GDC-0941 does not improve mtm motor function (45% WT, P < 0.001). In contrast, mtm motor function is improved relative to cognate-treated WT siblings by treatment with LY294002 (74% WT, P = 0.0059), wortmannin (70% WT, P = 0.0012), and, surprisingly, VPS34-IN1 (73% WT, P = 0.0155). Though these groups remained significantly different from WT, this improvement suggests an mtm-specific chemical effect for this phenotype (**P < 0.01, ***P < 0.001). Notably, mutants treated with PI-103 are statistically indistinguishable from PI-103–treated WT siblings (80% WT) and move significantly better than DMSO-treated mtm (*P < 0.0171). n = 24 each group; 2-way ANOVA, followed by Tukey’s post-test. (C) Kaplan-Meier survival curve showing that treatment with LY294002, wortmannin, and PI-103 improves median survival from 8 to 9 days and maximum survival from 9 to 11 to 12 days in comparison with DMSO-treated mtm larvae (P < 0.001 compared with mtm DMSO, Mantel-Cox or Gehan-Breslow-Wilcoxon tests). Inset legend top to bottom: n = 132, 43, 46, 47, 44.