Sonic hedgehog regulates its own receptor on postcrossing commissural axons in a glypican1-dependent manner.
Upon reaching their intermediate target, the floorplate, commissural axons acquire responsiveness to repulsive guidance cues, allowing the axons to exit the midline and adopt a contralateral, longitudinal trajectory. The molecular mechanisms that regulate this switch from attraction to repulsion remain poorly defined. Here, we show that the heparan sulfate proteoglycan Glypican1 (GPC1) is required as a coreceptor for the Shh-dependent induction of Hedgehog-interacting protein (Hhip) in commissural neurons. In turn, Hhip is required for postcrossing axons to respond to a repulsive anteroposterior Shh gradient. Thus, Shh is a cue with dual function. In precrossing axons it acts as an attractive guidance molecule in a transcription-independent manner. At the same time, Shh binds to GPC1 to induce the expression of its own receptor, Hhip, which mediates the repulsive response of postcrossing axons to Shh. Our study characterizes a molecular mechanism by which navigating axons switch their responsiveness at intermediate targets.
Institute of Molecular Life Sciences, Neuroscience Center Zurich, University of Zurich, CH-8057 Zurich, Switzerland.
Nicole H
NH
Wilson
Esther T
ET
Stoeckli
D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D007839:Functional Laterality / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D054259:Neural Tube / Q000166:cytology / Q000196:embryology; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D053673:Glypicans; D049452:Green Fluorescent Proteins; D008562:Membrane Glycoproteins; D035683:MicroRNAs; C498447:Hhip protein, mouse; C485184:enhanced green fluorescent protein