Editors' ChoiceNeuroscience

Programming Neuronal Regeneration

Science Signaling  19 Nov 2013:
Vol. 6, Issue 302, pp. ec280
DOI: 10.1126/scisignal.2004919

Although nerves in the central nervous system (CNS) do not regenerate after injury, nerves in the peripheral nervous system, such as sensory neurons or motor neurons, can. This regeneration process involves calcium signals and retrograde transport of signals from the injury site to the cell body and initiation of a proregeneration transcriptional profile. Alterations in histone acetylation, which is dynamically controlled by histone acetyltransferases (HATs) and histone deacetylates (HDACs), are one mechanism to trigger transcriptional reprogramming. HDAC5 is a substrate for protein kinase C (PKC) in injured neurons. Cho et al. examined the role of HDAC5 in the neuronal regeneration response to injury in dorsal root ganglion (DRG) neurons (peripheral neurons) and retinal ganglion cells (RGCs, a model for CNS neurons) in vivo and in culture. Axon cutting (axotomy) of cultured DRG neurons or sciatic nerve injury in vivo triggered calcium-dependent phosphorylation (and activation) of PKCμ, whereas optic nerve injury did not trigger phosphorylation of PKCμ in RGCs. Analysis of trafficking of green fluorescent protein (GFP)–tagged HDAC5 in cultured DRGs after injury revealed that the abundance of HDAC5 in the nucleus decreased. Western blot analysis of the abundance of HDAC5 in the soma or nerve segment near the injury site in mice with sciatic nerve injury also showed that the abundance of HDAC5 in the soma decreased, whereas its abundance near the injury site increased. Optic nerve injury did not increase HDAC5 abundance near the site of injury in RGCs. In peripheral nerves in vitro and in vivo, consistent with the apparent relocalization of HDAC5 from nucleus to injury site (where HDAC5 acetylates microtubules to contribute to promoting growth cone dynamics), the amount of acetylated histone H3 increased. In contrast, acetylated histone H3 abundance decreased after nerve injury in the RGCs in vivo. Knockdown of PKCµ prevented HDAC5 relocalization to the axons in axotomized cultured DRG neurons, and activation of PKCs with ingenol 3-angelate (I3A) stimulated nuclear export in the absence of injury. Expression of a mutant HDAC5 that was retained in the nucleus suppressed axon regeneration of injured cultured DRG neurons, and the regenerative capacity of HDAC5-knockdown neurons was restored by a cytosolic-localized HDAC5 mutant but not the nuclear-localized mutant. Transcriptional microarray analysis confirmed the importance of HDAC5 nuclear export in producing a profile with proregenerative characteristics. In vivo sciatic nerve injury studies examining DRG regeneration or motor neuron regeneration revealed that I3A injection increased the number of axons that regenerated past the injury site (in DRGs) or an increase in the number of reinnervated neuromuscular junctions. Thus, HDAC5 exhibits two key functions in peripheral nerve regeneration: When exported out of the nucleus, HDAC5 enables transcriptional reprogramming to promote regeneration and at the grown cone HDAC5 stimulates cytoskeletal dynamics to promote growth cone migration.

Y. Cho, R. Sloutsky, K. M. Naegle, V. Cavalli, Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell 155, 894–908 (2013). [PubMed]