FIGURE SUMMARY
Title

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

Authors
Al-Olabi, L., Polubothu, S., Dowsett, K., Andrews, K.A., Stadnik, P., Joseph, A.P., Knox, R., Pittman, A., Clark, G., Baird, W., Bulstrode, N., Glover, M., Gordon, K., Hargrave, D., Huson, S.M., Jacques, T.S., James, G., Kondolf, H., Kangesu, L., Keppler-Noreuil, K.M., Khan, A., Lindhurst, M.J., Lipson, M., Mansour, S., O'Hara, J., Mahon, C., Mosica, A., Moss, C., Murthy, A., Ong, J., Parker, V.E., Rivière, J.B., Sapp, J.C., Sebire, N.J., Shah, R., Sivakumar, B., Thomas, A., Virasami, A., Waelchli, R., Zeng, Z., Biesecker, L.G., Barnacle, A., Topf, M., Semple, R.K., Patton, E.E., Kinsler, V.A.
Source
Full text @ Journal of Clin. Invest.
Fig. 5

(A) Schematic of zebrafish embryos injected with Tg (fli1a:GFP) at the 1-cell stage generate zebrafish larvae that are mosaic for the transgene integration and expression. (B) Image of mosaic expression of Tg (fli1a:GFP) in a vessel. (C) Images of zebrafish expressing WT or mutant BRAFV600E in a mosaic fashion from a fli1a promoter in endothelial cells. Accumulation of blood is visible at the caudal vein vascular plexus in the BRAFV600E–expressing zebrafish and outlined with a dashed red line. (D) Quantification of VM phenotype in BRAFWT-expressing (n = 511) and BRAFV600E-expressing (n = 779) zebrafish. (E) BRAFWT and BRAFV600E mosaic expression in stable Tg (fli1a:GFP) larvae to visualize all vessels in the zebrafish in the VM lesion. Increased numbers of vascular channels and disorganized architecture of VM lesions are clearly detectable. (F) Schematic of VM treatment protocol and quantification of the percentage of VM BRAFV600E zebrafish with improved blood flow following treatment with vemurafenib. VM BRAFV600E zebrafish were randomized prior to DMSO (n = 31) or vemurafenib (n = 19) treatment and blind scored. (G) Images of zebrafish expressing MAPK2K1Q58del in a mosaic fashion from a fli1a promoter in endothelial cells (n = 5/37). Zebrafish larvae in D were analyzed by an unpaired parametric t test with Welch’s correction and in F by a paired t test comparing matched pairs (before and after treatment). Data are shown as SEM. ***P < 0.001.

Fig. S1

the effects of BRAF overexpression on tail development in zebrafish larvae. (a) Image of an example of a zebrafish larvae expressing high levels of MAPK signaling, leading to a "stunting" phenotype, as previously described(1, 2) (b) Graph of zebrafish embryos expressing BRAF WT or V600E alleles. Both WT and mutant alleles lead to a stunted phenotype that confounds analysis of the vasculature in those animals, and were excluded from further analysis.

Acknowledgments
This image is the copyrighted work of the attributed author or publisher, and ZFIN has permission only to display this image to its users. Additional permissions should be obtained from the applicable author or publisher of the image. Full text @ Journal of Clin. Invest.
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