Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits

Nat Commun. 2017 Feb 22:8:14508. doi: 10.1038/ncomms14508.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Axons / metabolism*
  • Blood Vessels / metabolism*
  • Body Patterning
  • Cell Adhesion Molecules, Neuronal / chemistry
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cell Membrane / metabolism
  • Cytoskeletal Proteins
  • Endocytosis*
  • Endosomes / metabolism
  • Epistasis, Genetic
  • Female
  • Glycoproteins / metabolism
  • Green Fluorescent Proteins / metabolism
  • Growth Cones / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • PDZ Domains
  • Protein Transport
  • Semaphorins
  • Signal Transduction*
  • ras Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Adhesion Molecules, Neuronal
  • Cytoskeletal Proteins
  • Glycoproteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PLXND1 protein, human
  • Plxnd1 protein, mouse
  • Sema3e protein, mouse
  • Semaphorins
  • Green Fluorescent Proteins
  • ras Proteins