Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits.
Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits.
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DOI：
10.1038/ncomms14508
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发表时间：
2017-02-22
影响因子：
16.6
通讯作者：
Mann F
中科院分区：
文献类型：
--
作者：
Burk K;Mire E;Bellon A;Hocine M;Guillot J;Moraes F;Yoshida Y;Simons M;Chauvet S;Mann F
涉及轴突引导信号受体的局部内吞事件在控制生长锥行为中起核心作用。然而，对于内化受体的命运，以及引导它们进入不同内体途径的分选事件是否控制着指导决策，我们知之甚少。在这里，我们发现受体Plexin-D1包含一个与接头蛋白GIPC1相互作用的分类基序，以促进转运到再循环的核内体。这种分选过程促进丛状蛋白d1与活性R-ras囊泡池共定位，导致其失活。在缺乏与GIPC1相互作用的情况下，Plexin-D1的错误分类导致信号活性的丧失。因此，Gipc1突变小鼠在轴突投射和血管结构上表现出特定的缺陷，这些缺陷依赖于丛状蛋白d1信号的发育。因此，通过内吞作用受体内化后发生的细胞内分选步骤为细胞对引导信号的反应提供了关键水平的控制。控制轴突生长锥体行为的分子机制只被部分理解。在这里，作者揭示了接头蛋白GIPC1在丛蛋白d1受体循环中的作用，并表明这一过程是小鼠轴突轨道形成和血管模式所必需的。
Local endocytic events involving receptors for axon guidance cues play a central role in controlling growth cone behaviour. Yet, little is known about the fate of internalized receptors, and whether the sorting events directing them to distinct endosomal pathways control guidance decisions. Here, we show that the receptor Plexin-D1 contains a sorting motif that interacts with the adaptor protein GIPC1 to facilitate transport to recycling endosomes. This sorting process promotes colocalization of Plexin-D1 with vesicular pools of active R-ras, leading to its inactivation. In the absence of interaction with GIPC1, missorting of Plexin-D1 results in loss of signalling activity. Consequently, Gipc1 mutant mice show specific defects in axonal projections, as well as vascular structures, that rely on Plexin-D1 signalling for their development. Thus, intracellular sorting steps that occur after receptor internalization by endocytosis provide a critical level of control of cellular responses to guidance signals. Molecular mechanisms controlling axonal growth cone behaviour are only partially understood. Here the authors reveal a role of an adaptor protein GIPC1 in Plexin-D1 receptor recycling, and show that this process is required for axon track formation and vascular patterning in mice.