title: 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing.
abstract: Axons must switch responsiveness to guidance cues during development for correct pathfinding. Sonic Hedgehog (Shh) attracts spinal cord commissural axons ventrally toward the floorplate. We show that after crossing the floorplate, commissural axons switch their response to Shh from attraction to repulsion, so that they are repelled anteriorly by a posterior-high/anterior-low Shh gradient along the longitudinal axis. This switch is recapitulated in vitro with dissociated commissural neurons as they age, indicating that the switch is intrinsic and time dependent. 14-3-3 protein inhibition converted Shh-mediated repulsion of aged dissociated neurons to attraction and prevented the correct anterior turn of postcrossing commissural axons in vivo, an effect mediated through PKA. Conversely, overexpression of 14-3-3 proteins was sufficient to drive the switch from Shh-mediated attraction to repulsion both in vitro and in vivo. Therefore, we identify a 14-3-3 protein-dependent mechanism for a cell-intrinsic temporal switch in the polarity of axon turning responses.
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Yam
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Kent
authors.forename: Steves
authors.initials: S
authors.lastname: Morin
authors.forename: W Todd
authors.initials: WT
authors.lastname: Farmer
authors.forename: Ricardo
authors.initials: R
authors.lastname: Alchini
authors.forename: Léa
authors.initials: L
authors.lastname: Lepelletier
authors.forename: David R
authors.initials: DR
authors.lastname: Colman
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: Alyson E
authors.initials: AE
authors.lastname: Fournier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis; D002645:Chickens; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018274:Electroporation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000145:classification / Q000166:cytology* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D018139:Simplexvirus / Q000235:genetics; D013119:Spinal Cord Injuries / Q000473:pathology*; D013997:Time Factors; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D000596:Amino Acids; D001426:Bacterial Proteins; D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008164:Luminescent Proteins; D010879:Piperazines; D020033:Protein Isoforms; D011720:Pyrazoles; D011758:Pyrroles; D034741:RNA, Small Interfering; D051155:Wnt1 Protein; D000075746:Zinc Finger Protein Gli2; D001616:beta-Galactosidase; C500943:Atoh1 protein, mouse; C000618551:Gli2 protein, mouse; C489536:Hip1 protein, mouse; C468919:SANT-1 compound; C465570:Shh protein, mouse; C098463:dolaisoleucine; C054562:yellow fluorescent protein, Bacteria; C057416:KT 5720