Promotion of Axon Growth by the Secreted End of a Transcription Factor

Axon growth is regulated externally by attractive and repulsive cues generated in the environment. In addition, intrinsic pathways govern axon development, although the extent to which axons themselves can influence their own growth is unknown. We find that dorsal root ganglion (DRG) axons secrete a factor supporting axon growth and identify it as the C terminus of the ER stress-induced transcription factor CREB3L2, which is generated by site 2 protease (S2P) cleavage in sensory neurons. S2P and CREB3L2 knockdown or inhibition of axonal S2P interfere with the growth of axons, and C-terminal CREB3L2 is sufficient to rescue these effects. C-terminal CREB3L2 forms a complex with Shh and stabilizes its association with the Patched-1 receptor on developing axons. Our results reveal a neuron-intrinsic pathway downstream of S2P that promotes axon growth.