Modeling Blood-Cns Barriers In Zebrafish

The blood-brain barrier (BBB) plays an important role in the treatment of brain tumors. Yet, a comprehensive understanding of brain tumor vasculaturization has been hampered by difficulties in observing this process in vivo. Recently, we have generated several models of brain tumors in zebrafish. To visualize the vascularization of these tumors, we generated transgenic zebrafish lines to serve as in vivo reporters of brain tumor vasculature. We show that our BBB transgenic line drives expression specifically in brain endothelial cells and not in the vasculature of peripheral tissues or circumventricular organs. Using time-lapse confocal microscopy, we find that barriergenesis (i.e. the initiation of BBB development) occurs immediately as new vessels sprout into the brain parenchyma. Using a combination of genetic and chemical tools, we demonstrate that canonical Wnt signaling, but not VEGF signaling, is essential for barriergenesis. These results indicate that CNS angiogenesis and barriergenesis occur simultaneously, but require distinct signals for proper formation. Furthermore, we created a complementary transgenic line that drives expression in fenestrated endothelium, a hallmark of brain tumor vasculature. The combination of these transgenic lines along with our newly developed tumor models will allow us to visualize the complexities of brain tumor vascularization in a live animal model. Citation Format: Robyn A. Umans, Hannah E. Henson, Chaithanyarani Parupalli, Bensheng Ju, Michael R. Taylor. Modeling blood-CNS barriers in zebrafish. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA19.