Polarized Dock Activity Drives Shh-Mediated Axon Guidance

Dev Cell. 2018 Aug 20;46(4):410-425.e7. doi: 10.1016/j.devcel.2018.07.007. Epub 2018 Aug 2.


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.

Keywords: Dock; Elmo; GEFs; axon guidance; commissural neurons; sonic hedgehog.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Axon Guidance / drug effects*
  • Axons / drug effects*
  • Carrier Proteins / genetics
  • Cells, Cultured
  • Cytoskeletal Proteins / genetics
  • Embryo, Mammalian / metabolism
  • GTPase-Activating Proteins / genetics
  • Gene Expression Regulation, Developmental / drug effects*
  • Gene Expression Regulation, Developmental / genetics
  • Growth Cones / drug effects
  • Growth Cones / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Hedgehog Proteins / metabolism
  • Hedgehog Proteins / pharmacology*
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Neurons / metabolism
  • Spinal Cord / metabolism


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Dock3 protein, mouse
  • Dock4 protein, mouse
  • ELMO1 protein, mouse
  • Elmo2 protein, mouse
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • Hedgehog Proteins
  • Nerve Tissue Proteins
  • Shh protein, mouse