Ethan P McCurdy1, Kyung Min Chung2, Carlos R Benitez-Agosto2, Ulrich Hengst3. 1. Integrated Program in Cellular, Molecular and Biomedical Studies, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. 2. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. 3. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: uh2112@cumc.columbia.edu.
Abstract
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.
Axon growth is regulated externally by attractive and repulsive cues generated in the envin class="Gene">ronment. 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.
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