title: Sonic Hedgehog Guides Axons via Zipcode Binding Protein 1-Mediated Local Translation.
abstract: Sonic hedgehog (Shh) attracts spinal cord commissural axons toward the floorplate. How Shh elicits changes in the growth cone cytoskeleton that drive growth cone turning is unknown. We find that the turning of rat commissural axons up a Shh gradient requires protein synthesis. In particular, Shh stimulation increases β-actin protein at the growth cone even when the cell bodies have been removed. Therefore, Shh induces the local translation of β-actin at the growth cone. We hypothesized that this requires zipcode binding protein 1 (ZBP1), an mRNA-binding protein that transports β-actin mRNA and releases it for local translation upon phosphorylation. We found that Shh stimulation increases phospho-ZBP1 levels in the growth cone. Disruption of ZBP1 phosphorylationin vitroabolished the turning of commissural axons toward a Shh gradient. Disruption of ZBP1 functionin vivoin mouse and chick resulted in commissural axon guidance errors. Therefore, ZBP1 is required for Shh to guide commissural axons. This identifies ZBP1 as a new mediator of noncanonical Shh signaling in axon guidance.SIGNIFICANCE STATEMENTSonic hedgehog (Shh) guides axons via a noncanonical signaling pathway that is distinct from the canonical Hedgehog signaling pathway that specifies cell fate and morphogenesis. Axon guidance is driven by changes in the growth cone in response to gradients of guidance molecules. Little is known about the molecular mechanism of how Shh orchestrates changes in the growth cone cytoskeleton that are required for growth cone turning. Here, we show that the guidance of axons by Shh requires protein synthesis. Zipcode binding protein 1 (ZBP1) is an mRNA-binding protein that regulates the local translation of proteins, including actin, in the growth cone. We demonstrate that ZBP1 is required for Shh-mediated axon guidance, identifying a new member of the noncanonical Shh signaling pathway.
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada H2W 1R7.
authors.forename: Léa
authors.initials: L
authors.lastname: Lepelletier
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada H2W 1R7.|Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3A 1A3.
authors.forename: Sébastien D
authors.identifier: 0000-0002-3553-5414
authors.initials: SD
authors.lastname: Langlois
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada H2W 1R7.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Kent
authors.affiliation: Department of Biological Sciences and.|School of Biomedical Sciences, Kent State University, Kent, Ohio 44242.
authors.forename: Kristy
authors.identifier: 0000-0001-6624-4719
authors.initials: K
authors.lastname: Welshhans
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada H2W 1R7.
authors.forename: Steves
authors.initials: S
authors.lastname: Morin
authors.affiliation: Department of Cell Biology and.|Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada H2W 1R7, patricia.yam@ircm.qc.ca Frederic.Charron@ircm.qc.ca.
authors.forename: Patricia T
authors.identifier: 0000-0002-3631-3151
authors.initials: PT
authors.lastname: Yam
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada H2W 1R7, patricia.yam@ircm.qc.ca Frederic.Charron@ircm.qc.ca.|Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada H3A 1A3.|Department of Anatomy and Cell Biology, Department of Biology, McGill University, Quebec, Canada H3A 2B2, and.|Department of Medicine, University of Montreal, Montreal, Quebec, Canada H3T 1J4.
authors.forename: Frédéric
authors.identifier: 0000-0003-3483-8672
authors.initials: F
authors.lastname: Charron
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D002645:Chickens; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D014176:Protein Biosynthesis / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology
chemical_list: D000199:Actins; C519161:CRD-BP protein, mouse; D006023:Glycoproteins; D053823:Hedgehog Proteins; D016601:RNA-Binding Proteins; C402632:Zbp1 protein, mouse
keywords: Sonic hedgehog; ZBP1; axon guidance; local translation