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Akt and PP2A Reciprocally Regulate the Guanine Nucleotide Exchange Factor Dock6 to Control Axon Growth of Sensory Neurons

The phosphorylation status of Dock6 causes sensory neuron axons to switch from extension to branching. Switching from Axon Extension to Branching Understanding the signaling pathways that enable neurons, such as dorsal root ganglion neurons, to extend axons into the periphery can identify potential therapeutic targets to promote nerve regeneration after injury. Miyamoto et al. found that the guanine nucleotide exchange factor Dock6, which regulates the cytoskeleton, was required for axonal extension during development and after nerve crush injury. Phosphorylation of Dock6 by the kinase Akt inhibited its activity; dephosphorylation by the phosphatase PP2A promoted Dock6 activity. During development, peripheral sensory neurons extend axons until the axons contact their targets, at which point they branch. During developmental stages when axons were growing, extending periods were associated with the interaction of PP2A with Dock6 and low Dock6 phosphorylation, whereas periods of branching were associated with the interaction of Akt with Dock6 and high Dock6 phosphorylation. Rescue experiments indicated that the phosphorylation status of Dock6 switched dorsal root ganglion neurons from axon extension to branching. Thus, regulation of the phosphorylation status of Dock6 by Akt and PP2A determines whether it promotes axon extension or branching in dorsal root ganglion neurons, and timing of treatments targeting this pathway for nerve regeneration is essential to proper reinnervation. During neuronal development, axons navigate long distances, eventually forming precise connections with such targets as peripheral tissues. Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. We found that phosphorylation of Ser1194 in Dock6 inhibited its GEF activity and suppressed axonal growth of embryonic sensory neurons and axon regeneration of postnatal sensory neurons in vitro and in vivo. At early developmental stages, when axons are growing, the protein phosphatase PP2A interacted with and dephosphorylated Dock6, thereby increasing the activity of Dock6. At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser1194. In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching. Thus, the phosphorylation status of Dock6 at Ser1194 determines whether it promotes axon extension or branching in sensory neurons, revealing interplay between kinase and phosphatase action on a Rho-GEF during axon growth.