Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing

Nat Neurosci. 2010 Jan;13(1):29-35. doi: 10.1038/nn.2457. Epub 2009 Nov 29.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Axons / drug effects
  • Axons / physiology*
  • Body Patterning / drug effects
  • Body Patterning / genetics
  • Body Patterning / physiology*
  • Cell Movement / physiology
  • Cells, Cultured
  • Chlorocebus aethiops
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Embryo, Mammalian
  • Functional Laterality / genetics
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / physiology
  • Green Fluorescent Proteins / genetics
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / immunology
  • Hedgehog Proteins / physiology*
  • Mice
  • Mutation / genetics
  • Neurons / cytology*
  • Neurons / drug effects
  • Neuropilin-2 / genetics
  • Organ Culture Techniques
  • Patched Receptors
  • Patched-1 Receptor
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Receptors, Cell Surface / genetics
  • Semaphorins / genetics
  • Semaphorins / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Spinal Cord / cytology
  • Spinal Cord / embryology
  • Transfection / methods

Substances

  • Antibodies, Monoclonal
  • Hedgehog Proteins
  • Neuropilin-2
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Ptch1 protein, rat
  • Receptors, Cell Surface
  • Semaphorins
  • Green Fluorescent Proteins
  • Colforsin
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases