Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Nat Commun. 2017 Feb 22;8:14508. doi: 10.1038/ncomms14508.
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.
局部内吞事件涉及到轴突导向线索的受体，在控制生长锥行为方面起着核心作用。然而，对于内化的受体的命运，以及指导它们进入不同内体途径的分选事件是否控制导向决策，我们知之甚少。在这里，我们表明 Plexin-D1 受体含有一个分选基序，该基序与衔接蛋白 GIPC1 相互作用，促进其向再循环内体的运输。这个分选过程促进了 Plexin-D1 与活性 R-ras 的囊泡池的共定位，导致其失活。在与 GIPC1 没有相互作用的情况下，Plexin-D1 的错误分选导致信号活性丧失。因此，GIPC1 突变小鼠在轴突投射以及依赖 Plexin-D1 信号通路发育的血管结构方面表现出特定的缺陷。因此，内吞作用后发生的细胞内分选步骤为细胞对导向信号的反应提供了一个关键的控制水平。
