title: Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing.
abstract: Pathfinding axons change responses to guidance cues at intermediate targets. During midline crossing, spinal cord commissural axons acquire responsiveness to class 3 Semaphorins and Slits, which regulate their floor plate exit and restrict their post-crossing trajectory into a longitudinal pathway. We found that Sonic Hedgehog (Shh) could activate the repulsive response of pre-crossing axons to Semaphorins. Blocking Shh function with a monoclonal antibody to Shh, 5E1, in 'open-book' explants or by expressing a dominant-negative form of Patched-1, Ptch1(Delta loop2), or a Smoothened (Smo) shRNA construct in commissural neurons resulted in severe guidance defects, including stalling and knotting inside the floor plate, recrossing, randomized anterior-posterior projection and overshooting after crossing, reminiscent of Neuropilin-2 mutant embryos. Enhancing protein kinase A activity in pre-crossing axons diminished Shh-induced Semaphorin repulsion and caused profound midline stalling and overshooting/wandering of post-crossing axons. Therefore, a morphogen, Shh, can act as a switch of axon guidance responses.
authors: Neurobiology Section, Biological Sciences Division, University of California San Diego, La Jolla, California, USA.
authors: Liseth M
authors: LM
authors: Parra
authors: Yimin
authors: Y
authors: Zou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004622:Embryo, Mammalian; D007839:Functional Laterality / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D039943:Neuropilin-2 / Q000235:genetics; D009924:Organ Culture Techniques; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011956:Receptors, Cell Surface / Q000235:genetics; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D014162:Transfection / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D053823:Hedgehog Proteins; D039943:Neuropilin-2; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; D011956:Receptors, Cell Surface; D039961:Semaphorins; D049452:Green Fluorescent Proteins; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases