Abstract
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.
Highlights
The complex neuronal network is in part assembled through the stepwise events of axon pathfinding
We report here that Sonic Hedgehog (Shh)–Smoothened (Smo) signaling activates planar cell polarity (PCP) signaling by inhibiting the expression of Shisa2, an inhibitor of Wnt signaling that blocks Frizzled3 (Fzd3) glycosylation and cell-surface presentation
As Shh is a major signaling molecule in the ventral midline, we hypothesized that Shh signaling may regulate the expression of genes relevant to the switch of responsiveness of commissural neurons during midline crossing
Summary
The complex neuronal network is in part assembled through the stepwise events of axon pathfinding. Many axonal growth cones follow the instruction of a set of guidance cues until they reach their intermediate targets; they switch their responsiveness to follow new guidance cues which allow them to navigate to the intermediate targets (or the final targets). The mechanisms of these important switches are not well understood. Wnts are expressed in a decreasing anterior-to-posterior gradient in the floor plate and direct the post-crossing commissural axons to turn anteriorly after midline crossing (Lyuksyutova et al, 2003). We report here that Shh–Smoothened (Smo) signaling activates PCP signaling by inhibiting the expression of Shisa, an inhibitor of Wnt signaling that blocks Frizzled (Fzd3) glycosylation and cell-surface presentation
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