title: Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits.
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.
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Katja
authors.initials: K
authors.lastname: Burk
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Erik
authors.initials: E
authors.lastname: Mire
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Bellon
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Hocine
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Guillot
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Filipa
authors.initials: F
authors.lastname: Moraes
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.|Department of Cell Biology Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Michael
authors.identifier: 0000-0003-0348-7734
authors.initials: M
authors.lastname: Simons
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chauvet
authors.affiliation: Aix Marseille Univ, CNRS, IBDM, Marseille 13288, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Mann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001808:Blood Vessels / Q000378:metabolism*; D019521:Body Patterning; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D054731:PDZ Domains; D021381:Protein Transport; D039961:Semaphorins; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C493082:PLXND1 protein, human; C473552:Plxnd1 protein, mouse; C111150:Sema3e protein, mouse; D039961:Semaphorins; D049452:Green Fluorescent Proteins; D018631:ras Proteins