Valeria Cavalli, PhD
Professor of Neuroscience
Molecular, cellular and epigenetic mechanisms regulating axon regeneration Read More
|Lab Phone:||(314) 362-3540|
|Lab Location:||McDonnell Sciences 452|
|Keywords:||axon regeneration, axonal transport, cell biology of the axon, in vitro and in vivo regeneration/transport assays, live imaging|
Molecular, cellular and epigenetic mechanisms regulating axon regeneration
Cultured sensory neurons were injured and stained with acetylated tubulin (green), alpha tubulin (red) and GAP43 (blue). Tubulin deacetylation occurs at the site of injury, a process required for axon regeneration.
The major goal in the Cavalli lab is to understand the mechanisms by which peripheral nervous system (PNS) neurons regenerate to identify potential targets for future therapeutic interventions in the setting of central nervous system (CNS) injury and under conditions of traumatic PNS injuries. To elucidate the molecular mechanisms of axon regeneration in the mouse model system, we are employing biochemical, molecular, cell biological, live imaging, and genetic approaches.
We have initially focused on the issue of retrograde injury signaling, or how information about an injury is conveyed from the distantly located lesion site in the axon back to the cell body. We have discovered aspects of this mechanism that include the retrograde transport of organelles bearing the adaptor protein Sunday Driver (syd, also known as JIP3) on their surface and the role of the DLK/JNK signaling pathway in injury signaling and axon regeneration. We are following these studies to uncover the detailed signaling pathways controlling axon to soma communication following neuronal injury.
In pursuing our studies on the response of axons to injury, we turned our attention to the microtubule tracks on which vesicles and organelles are transported along axons. These studies led us to discover that injury to peripheral, but not central neurons induces microtubule post-translational modifications, with a decrease in tubulin acetylation. Indeed, we demonstrated that the histone deacetylase HDAC5 is a novel injury-regulated tubulin deacetylase controlling growth cone dynamics and axon regeneration. This work suggests that injury-induced tubulin deacetylation may govern the repair of damaged axon tips and their transformation into growth cones. In addition to tubulin deacetylation, we also reported increased tubulin tyrosination at the site of axon injury and our recent data suggest that tubulin tyrosination may function to initiate retrograde transport of injury signals that are required for the activation of the pro-regenerative program. These findings point to the important roles of microtubule posttranslational modifications in the ability of injured axons to regenerate.
Axon regeneration following nerve injury critically depends on the ability of injured neurons to activate a pro-regenerative program. We found that axon injury induces HDAC5 nuclear export and thereby elicits an epigenetic switch controlling regenerative competence in adult sensory neurons. We also demonstrated that following peripheral nerve injury activation of the evolutionarily conserved mammalian Target Of Rapamycin (mTOR) is sufficient to sustain regenerative growth of peripheral nerves. We are pursuing our studies to uncover epigenetic, transcriptional and translational pathways that are induced by axon injury and culminate in the activation of a pro-regenerative program.
The ongoing research efforts in my laboratory thus explore the injury-induced pathways elicited in both cell body and in the axon that enable axon regeneration. We are currently building on our discoveries to unravel the molecular events that dictate the regenerative response of peripheral neurons with the goal to identify potential targets for future therapeutic interventions in the context of CNS injury.
Updated January 2014
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