Robo4 is a vascular-specific receptor that inhibits endothelial migration
Robo4 is a vascular-specific receptor that inhibits endothelial migration
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DOI：
10.1016/s0012-1606(03)00258-6
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发表时间：
2003-09-01
影响因子：
2.7
通讯作者：
Li, DY
中科院分区：
文献类型：
--
作者：
Park, KW;Morrison, CM;Li, DY
轴突的引导和模式是由提供方向线索的细胞表面受体和配体协调的。Robo受体和狭缝配体蛋白家族之间的相互作用启动了排斥轴突生长的信号级联反应。尽管血管和神经系统以平行网络的方式生长，但血管内皮细胞被引导到适当位置的机制仍然不清楚。我们已经确定了一个假定的Robo同源物Robo4，基于其在血管发芽缺陷的突变小鼠中的差异表达。与已知的神经元Robo家族成员相比，Robo4的细胞外结构域的排列与所有其他Robo家族成员明显不同。此外，Robo4在小鼠胚胎发育过程中在血管内皮中特异性表达。我们发现Robo4结合Slit并在异源表达系统中抑制细胞迁移，类似于已知的Robo受体在神经系统中的作用。免疫沉淀研究表明，Robo4与Mena结合，这是一种已知的Robo-Slit信号效应物。最后，我们发现Robo4是唯一在原代内皮细胞中表达的Robo家族成员，并且Slit的应用抑制了它们的迁移。这些数据表明，Robo4是Robo家族的真正成员，可能在血管发育过程中为迁移内皮细胞提供排斥提示。(C) 2003 Elsevier Inc.版权所有。
Guidance and patterning of axons are orchestrated by cell-surface receptors and ligands that provide directional cues. Interactions between the Robo receptor and Slit ligand families of proteins initiate signaling cascades that repel axonal outgrowth. Although the vascular and nervous systems grow as parallel networks, the mechanisms by which the vascular endothelial cells are guided to their appropriate positions remain obscure. We have identified a putative Robo homologue, Robo4, based on its differential expression in mutant mice with defects in vascular sprouting. In contrast to known neuronal Robo family members, the arrangement of the extracellular domains of Robo4 diverges significantly from that of all other Robo family members. Moreover, Robo4 is specifically expressed in the vascular endothelium during murine embryonic development. We show that Robo4 binds Slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known Robo receptors in the nervous system. Immunoprecipitation studies indicate that Robo4 binds to Mena, a known effector of Robo-Slit signaling. Finally, we show that Robo4 is the only Robo family member expressed in primary endothelial cells and that application of Slit inhibits their migration. These data demonstrate that Robo4 is a bona fide member of the Robo family and may provide a repulsive cue to migrating endothelial cells during vascular development. (C) 2003 Elsevier Inc. All rights reserved.