Protein fucosylation is required for Notch dependent vascular integrity in zebrafish
Protein fucosylation is required for Notch dependent vascular integrity in zebrafish
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DOI：
10.1016/j.ydbio.2021.08.004
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发表时间：
2021-08-24
影响因子：
2.7
通讯作者：
French，Curtis R.
中科院分区：
文献类型：
--
作者：
Fowler，Gerissa;French，Danielle;French，Curtis R.
发育中的胚胎循环的开始需要完整的血管来防止出血。内皮细胞的发育及其随后的血管周壁细胞的募集是建立和维持血管完整性的重要过程。这些过程在发育过程中受到遗传控制，通过添加壁细胞影响内皮细胞特化、模式形成或成熟的突变可导致早期发育性出血。我们创建了一个功能缺失的等位基因，该等位基因是斑马鱼GDP-岩藻糖的新生合成所必需的，并且纯合子胚胎显示出大脑发育。我们的数据表明，在出血时观察到的异位分支，gmd突变体在血管模式上有早期缺陷。随后，观察到排列在脉管系统中的壁细胞数量的缺陷。此外，Notch信号的激活挽救了突变体的出血表型，突出了需要蛋白质岩藻糖基化以保持血管完整性的潜在下游途径。最后，补充岩藻糖可以挽救出血频率的个体，表明通过替代（挽救）途径合成GDP-岩藻糖可能提供一种治疗性纠正由于新生GDP-岩藻糖合成缺陷而观察到的表型的途径。总之，这些数据与新生和补救蛋白岩藻糖基化途径通过Notch依赖性机制调节血管完整性的新作用一致。
The onset of circulation in a developing embryo requires intact blood vessels to prevent hemorrhage. The development of endothelial cells, and their subsequent recruitment of perivascular mural cells are important processes to establish and maintain vascular integrity. These processes are genetically controlled during development, and mutations that affect endothelial cell specification, pattern formation, or maturation through the addition of mural cells can result in early developmental hemorrhage. We created a strong loss of function allele of the zebrafishGDP-mannose 4,6 dehydratase(gmds) gene that is required for thede novosynthesis of GDP-fucose, and homozygous embryos display cerebral hemorrhages. Our data demonstrate thatgmdsmutants have early defects in vascular patterning with ectopic branches observed at time of hemorrhage. Subsequently, defects in the number of mural cells that line the vasculature are observed. Moreover, activation of Notch signaling rescued hemorrhage phenotypes ingmdsmutants, highlighting a potential downstream pathway that requires protein fucosylation for vascular integrity. Finally, supplementation with fucose can rescue hemorrhage frequency ingmdsmutants, demonstrating that synthesis of GDP-fucose via an alternative (salvage) pathway may provide an avenue toward therapeutic correction of phenotypes observed due to defects inde novoGDP-fucose synthesis. Together, these data are consistent with a novel role for thede novoand salvage protein fucosylation pathways in regulating vascular integrity through a Notch dependent mechanism.