Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.
Netrins stimulate and orient axon growth through a mechanism requiring receptors of the DCC family. It has been unclear, however, whether DCC proteins are involved directly in signaling or are mere accessory proteins in a receptor complex. Further, although netrins bind cells expressing DCC, direct binding to DCC has not been demonstrated. Here we show that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation.
Department of Anatomy, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0452, USA.
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Stein
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Zou
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Poo
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Tessier-Lavigne
D000818:Animals; D001369:Axons / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D046508:Culture Techniques; D004625:Embryo, Nonmammalian; D020439:Growth Cones / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D000075386:Netrin Receptors; D000075388:Netrin-1; D009474:Neurons / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D043704:Receptor, Adenosine A2B; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014970:Xanthines / Q000494:pharmacology; D014981:Xenopus / Q000196:embryology
D015815:Cell Adhesion Molecules; D008024:Ligands; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617354:Ntn1 protein, rat; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D011956:Receptors, Cell Surface; D018047:Receptors, Purinergic P1; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D014970:Xanthines; D000075388:Netrin-1; D017228:Hepatocyte Growth Factor; C034347:enprofylline