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.
Stein
E
E
Department of Anatomy and Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
Tessier-Lavigne
M
M
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