Lack of robust axonal regeneration represents one of the major barriers to recovery of neurological functions following injury to neurons within the central nervous system (CNS). In contrast, neurons in the peripheral nervous system (PNS) have a remarkable ability to regenerate after injury. The extent of axonal regeneration not only depends on the presence or absence of inhibitory cues in the environment, but also on the intrinsic growth capacity of damaged neurons. Indeed, blocking extracellular inhibitory influences alone is not sufficient to allow complete axon regeneration, emphasizing the need for a better understanding of the mechanisms controlling the intrinsic regenerative ability of injured neurons. The mechanisms that govern axon regeneration operate both in the cell body and locally in the axon. The local axonal responses allow injured neurons to signal back to the cell body and to transform their damaged axonal tips into a new growth- cone-like structure, two processes that are essential to initiate regeneration. In pursuing our studies on the response of axons to injury, we recently focused on the microtubule (MT) cytoskeleton. We found that the histone deacetylase HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. HDAC5 accumulates and deacetylates tubulin at the tip of injured PNS, but not CNS axons. HDAC5-mediated tubulin deacetylation is essential for PNS neuron's ability to regenerate, but fails to occur in CNS neurons. In addition to tubulin deacetylation, we observed that PNS axon injury also increases tubulin tyrosination. Tubulin acetylation and tyrosination are known to contribute to the dynamics properties of MTs and to MT-dependent axonal transport. However, the signaling pathways elicited by injury, which regulate MT posttranslational modifications and the precise role these modifications play in axon regeneration remain elusive. Here we propose to uncover the mechanisms controlling MT post-translational modifications in injured axons and to establish their specific roles in injured axons. Specifically, we will determine how a tubulin deacetylation gradient is maintained over time to sustain axon regeneration. We will also determine whether tubulin tyrosination initiates the retrograde transport of injury signals to activate a pro- regenerative program. Our long-term goal is to gain new insights into the molecular events that dictate the regenerative response of PNS neurons, and identify potential targets for future therapeutic interventions in the setting of CNS injury.

Public Health Relevance

Lack of robust axon regeneration in the central nervous system (CNS) represents one of the major barriers to recovery of neurological functions following injury and remains a major problem in neurobiology. To solve this problem, our goal is to reveal the molecular pathways that dictate the regenerative response of PNS neurons, which successfully regenerate. Here we propose to test the hypothesis that injury-induced tubulin post-translational modifications in axons increase the growth capacity of peripheral neurons by promoting growth-cone formation and retrograde injury signaling.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Jakeman, Lyn B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Mahar, Marcus; Cavalli, Valeria (2018) Intrinsic mechanisms of neuronal axon regeneration. Nat Rev Neurosci 19:323-337
Ban, Norimitsu; Siegfried, Carla J; Lin, Jonathan B et al. (2017) GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients. JCI Insight 2:
Mogha, Amit; Harty, Breanne L; Carlin, Dan et al. (2016) Gpr126/Adgrg6 Has Schwann Cell Autonomous and Nonautonomous Functions in Peripheral Nerve Injury and Repair. J Neurosci 36:12351-12367
Saito, Atsushi; Cavalli, Valeria (2016) Signaling Over Distances. Mol Cell Proteomics 15:382-93
Cho, Yongcheol; Shin, Jung Eun; Ewan, Eric Edward et al. (2015) Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1?. Neuron 88:720-34
Cho, Yongcheol; Park, Dongeun; Cavalli, Valeria (2015) Filamin A is required in injured axons for HDAC5 activity and axon regeneration. J Biol Chem 290:22759-70
Watt, Dana; Dixit, Ram; Cavalli, Valeria (2015) JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation. J Biol Chem 290:15512-25
Song, Wenjun; Cho, Yongcheol; Watt, Dana et al. (2015) Tubulin-tyrosine Ligase (TTL)-mediated Increase in Tyrosinated ?-Tubulin in Injured Axons Is Required for Retrograde Injury Signaling and Axon Regeneration. J Biol Chem 290:14765-75
Cho, Yongcheol; Di Liberto, Valentina; Carlin, Dan et al. (2014) Syntaxin13 expression is regulated by mammalian target of rapamycin (mTOR) in injured neurons to promote axon regeneration. J Biol Chem 289:15820-32
Cho, Yongcheol; Cavalli, Valeria (2014) HDAC signaling in neuronal development and axon regeneration. Curr Opin Neurobiol 27:118-26

Showing the most recent 10 out of 11 publications