The Cytoskeletal Stress Response Pathway: a homeostatic system driven by Dual Leucine Zipper Kinase (DLK).

Injury to the cytoskeleton enhances the regenerative potential of axons. This response requires dual leucine zipper kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic system may exist. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that a) cytoskeletal perturbation activates DLK signaling and b) DLK signaling mitigates the microtubule damage caused by the cytoskeletal perturbation. We also perform RNA-seq to discover a DLK-dependent transcriptional signature. This signature includes genes likely to attenuate DLK signaling while simultaneously inducing actin regulating genes and promoting actin-based morphological changes to the axon. These results are consistent with the model that cytoskeletal disruption in the neuron induces a DLK-dependent homeostatic mechanism, which we term the Cytoskeletal Stress Response (CSR) pathway.