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Published on: January 12, 2014
Polarized Dock Activity Drives Shh-Mediated Axon Guidance
Shirin Makihara1, Steves Morin2, Julien Ferent2
1Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Ave West, Montreal, QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC H3A 2B4, Canada.
Abstract:
In the developing spinal cord, Sonic hedgehog (Shh) attracts commissural axons toward the floorplate. How Shh regulates the cytoskeletal remodeling that underlies growth cone turning is unknown. We found that Shh-mediated growth cone turning requires the activity of Docks, which are unconventional GEFs. Knockdown of Dock3 and 4, or their binding partner ELMO1 and 2, abolished commissural axon attraction by Shh in vitro. Dock3/4 and ELMO1/2 were also required for correct commissural axon guidance in vivo. Polarized Dock activity was sufficient to induce axon turning, indicating that Docks are instructive for axon guidance. Mechanistically, we show that Dock and ELMO interact with Boc, the Shh receptor, and that this interaction is reduced upon Shh stimulation. Furthermore, Shh stimulation translocates ELMO to the growth cone periphery and activates Rac1. This identifies Dock/ELMO as an effector complex of non-canonical Shh signaling and demonstrates the instructive role of GEFs in axon guidance.
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