Sonic Hedgehog switches on Wnt/planar cell polarity signaling in commissural axon growth cones by reducing levels of Shisa2

Elife. 2017 Sep 8;6:e25269. doi: 10.7554/eLife.25269.


Commissural axons switch on responsiveness to Wnt attraction during midline crossing and turn anteriorly only after exiting the floor plate. We report here that Sonic Hedgehog (Shh)-Smoothened signaling downregulates Shisa2, which inhibits the glycosylation and cell surface presentation of Frizzled3 in rodent commissural axon growth cones. Constitutive Shisa2 expression causes randomized turning of post-crossing commissural axons along the anterior-posterior (A-P) axis. Loss of Shisa2 led to precocious anterior turning of commissural axons before or during midline crossing. Post-crossing commissural axon turning is completely randomized along the A-P axis when Wntless, which is essential for Wnt secretion, is conditionally knocked out in the floor plate. This regulatory link between Shh and planar cell polarity (PCP) signaling may also occur in other developmental processes.

Keywords: Midline; Shisa2; Sonic hedgehog; Wnt; axon guidance; mouse; neuroscience; planar cell polarity.

MeSH terms

  • Animals
  • COS Cells
  • Cell Polarity*
  • Central Nervous System / embryology*
  • Chlorocebus aethiops
  • Frizzled Receptors / metabolism*
  • Gene Expression Regulation
  • Glycosylation
  • Growth Cones / physiology*
  • HEK293 Cells
  • Hedgehog Proteins / metabolism*
  • Humans
  • Membrane Proteins / metabolism*
  • Mice, Knockout
  • Rats
  • Wnt Signaling Pathway*


  • Frizzled Receptors
  • Fzd3 protein, mouse
  • Hedgehog Proteins
  • Membrane Proteins
  • Shisa protein, mouse