RETRACTED: Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex.
Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: They become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation.
Department of Anatomy and Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
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D000818:Animals; D001369:Axons / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D004625:Embryo, Nonmammalian / Q000166:cytology; D020439:Growth Cones / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins; D014981:Xenopus / Q000196:embryology; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D015815:Cell Adhesion Molecules; D017228:Hepatocyte Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein