A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development.
A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development.
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DOI：
10.1016/j.ydbio.2009.02.031
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发表时间：
2009-05-15
影响因子：
2.7
通讯作者：
Lawson, N. D.
中科院分区：
文献类型：
--
作者：
Covassin, L. D.;Siekmann, A. F.;Kacergis, M. C.;Laver, E.;Moore, J. C.;Villefranc, J. A.;Weinstein, B. M.;Lawson, N. D.
在这项工作中，我们描述了一种正向遗传学方法来识别影响斑马鱼血管发育的突变。通过在转基因背景中应用允许直接可视化血管的单倍体筛选策略，可以鉴定几类突变血管表型。随后对突变株的表征显示，血管内皮生长因子（VEGF）信号传导的缺陷特别影响动脉发育。与功能性斑马鱼VEGF受体-2直系同源物（称为kdr样，kdrl）内的不同突变相关的表型的比较揭示了对血管发育的令人惊讶的不同影响。同时，我们确定了磷脂酶C γ 1（plcg 1）的一系列等位基因突变。连同在体内的结构-功能分析，我们的研究结果表明，需要Plcg 1的受体酪氨酸激酶的催化活性下游。我们进一步发现，胚胎缺乏母体和合子plcg 1显示更严重的动脉分化缺陷，但在其他方面类似合子突变体。最后，我们通过镶嵌分析证明了plcg 1在内皮细胞中的自主功能。我们的遗传分析表明，VEGF/Plcg 1信号在多个时间点和不同的信号背景下起作用，以介导动脉发育的不同方面。
In this work we describe a forward genetic approach to identify mutations that affect blood vessel development in the zebrafish. By applying a haploid screening strategy in a transgenic background that allows direct visualization of blood vessels, it was possible to identify several classes of mutant vascular phenotypes. Subsequent characterization of mutant lines revealed that defects in Vascular endothelial growth factor (Vegf) signaling specifically affected artery development. Comparison of phenotypes associated with different mutations within a functional zebrafish Vegf receptor-2 ortholog (referred to as kdr-like, kdrl) revealed surprisingly varied effects on vascular development. In parallel, we identified an allelic series of mutations in phospholipase c gamma 1 (plcg1). Together with in vivo structure-function analysis, our results suggest a requirement for Plcg1 catalytic activity downstream of receptor tyrosine kinases. We further find that embryos lacking both maternal and zygotic plcg1 display more severe defects in artery differentiation but are otherwise similar to zygotic mutants. Finally, we demonstrate through mosaic analysis that plcg1 functions autonomously in endothelial cells. Together our genetic analyses suggest that Vegf/Plcg1 signaling acts at multiple time points and in different signaling contexts to mediate distinct aspects of artery development.
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影响因子：
56.9
作者：
Lammert, E;Cleaver, O;Melton, D
通讯作者：
Melton, D
影响因子：
16
作者：
Gerety, SS;Wang, HU;Anderson, DJ
通讯作者：
Anderson, DJ
DOI：
10.1073/pnas.0506886103
发表时间：
2006-04-25
影响因子：
11.1
作者：
Covassin, LD;Villefranc, JA;Lawson, ND
通讯作者：
Lawson, ND
影响因子：
11.8
作者：
Kawakami, K;Takeda, H;Mishina, M
通讯作者：
Mishina, M
斑马鱼VEGF受体：术语指南。
影响因子：
4.5
作者：
Bussmann, Jeroen;Lawson, Nathan;Zon, Leonard;Schulte-Merker, Stefan
通讯作者：
Schulte-Merker, Stefan