14-3-3 Proteins Regulate a Cell-Intrinsic Switch from Sonic Hedgehog-Mediated Commissural Axon Attraction to Repulsion after Midline Crossing

• Published in: Neuron (Cambridge, Mass.) Mass.), 2012-11, Vol.76 (4), p.735-749
• Main Authors: Yam, Patricia T., Kent, Christopher B., Morin, Steves, Farmer, W. Todd, Alchini, Ricardo, Lepelletier, Léa, Colman, David R., Tessier-Lavigne, Marc, Fournier, Alyson E., Charron, Frédéric
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - genetics; 14-3-3 Proteins - metabolism; Amino Acids; Analysis of Variance; Animals; Axons - drug effects; Axons - physiology; Bacterial Proteins - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Carbazoles - pharmacology; Cells, Cultured; Chemotaxis; Chickens; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electroporation; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Female; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Developmental - physiology; Green Fluorescent Proteins - genetics; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hedgehog Proteins - pharmacology; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Luminescent Proteins - genetics; Mammals; Medical research; Mice; Mice, Transgenic; Migration; Neurons; Neurons - classification; Neurons - cytology; Neurons - metabolism; Piperazines - pharmacology; Pregnancy; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Pyrazoles - pharmacology; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Rodents; Signal Transduction - drug effects; Simplexvirus - genetics; Spinal cord; Spinal Cord Injuries - pathology; Time Factors; Wnt1 Protein - genetics; Wnt1 Protein - metabolism; Zinc Finger Protein Gli2
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2012.09.017

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. ► Commissural axons have an intrinsic temporal switch from Shh attraction to repulsion ► Inhibition of 14-3-3 activity converts Shh-dependent axon repulsion to attraction ► 14-3-3 activity is required for guidance of postcrossing commissural axons in vivo ► 14-3-3 overexpression triggers premature switching from Shh attraction to repulsion Axons switch responsiveness to guidance cues as they navigate. Yam et al. show that a cell-intrinsic switch controls commissural axon responses to Shh. This switch is regulated by increased 14-3-3 protein levels, which converts Shh response from attraction to repulsion.