DeVault, L. | Search bioRxiv

bioRxiv2023

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

Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. 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 response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that a) low dose nocodazole treatment 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.

neuroscience↗

bioRxiv2021

Steroid hormone signaling activates thermal nociception during Drosophila peripheral nervous system development

Sensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development. Drosophila melanogaster larvae undergo a behavioral transition by robustly activating a thermal nociceptive escape behavior during the second half of larval development (3rd instar). The Class 4 dendritic arborization (C4da) neurons are multimodal sensors which tile the body wall of Drosophila larvae and detect nociceptive temperature, light, and mechanical force. In contrast to the increase in nociceptive behavior in the 3rd instar, we find that ultraviolet light-induced Ca2+ activity in C4da neurons decreases during same period of larval development. Loss of ecdysone receptor has previously been shown to reduce nociception in 3rd instar larvae. We find that ligand dependent activation of ecdysone signaling is sufficient to promote nociceptive responses in 2nd instar larvae and suppress expression of subdued (encoding a TMEM16 channel). Reduction of subdued expression in 2nd instar C4da neurons not only increases thermal nociception but also decreases the response to ultraviolet light. Thus, steroid hormone signaling suppresses subdued expression to facilitate the sensory switch of C4da neurons. This regulation of a developmental sensory switch through steroid hormone regulation of channel expression raises the possibility that ion channel homeostasis is a key target for tuning the development of sensory modalities.

neuroscience↗