HDAC signaling in neuronal development and axon regeneration - PubMed (original) (raw)

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HDAC signaling in neuronal development and axon regeneration

Yongcheol Cho et al. Curr Opin Neurobiol. 2014 Aug.

Abstract

The development and repair of the nervous system requires the coordinated expression of a large number of specific genes. Epigenetic modifications of histones represent an essential principle by which neurons regulate transcriptional responses and adapt to environmental cues. The post-translational modification of histones by chromatin-modifying enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs) shapes chromatin to adjust transcriptional profiles during neuronal development. Recent observations also point to a critical role for histone acetylation and deacetylation in the response of neurons to injury. While HDACs are mostly known to attenuate transcription through their deacetylase activity and their interaction with co-repressors, these enzymes are also found in the cytoplasm where they display transcription-independent activities by regulating the function of diverse proteins. Here we discuss recent studies that go beyond the traditional use of HDAC inhibitors and have begun to dissect the roles of individual HDAC isoforms in neuronal development and repair after injury.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. Comparison of classes I, II, III and IV HDAC protein structure and subcellular localization

All HDACs contain a highly conserved catalytic domain known as zinc-dependent histone deacetylases. Class IIa enzymes are characterized by an N-terminal extension not found in other classes I. The sirtuins represents class III but are functionally unrelated to HDACs as their deacetylase activity depends on the co-factor NAD+. HDAC6 is the only HDAC that contains an identical duplication of two catalytic domains. It was traditionally thought that class I HDACs are located in the nucleus, whereas class II HDACs can shuttle between the nucleus and the cytoplasm. However, many studies have shown that specific signal transduction pathways can regulate the cellular localization of various HDACs, including class I HDACs. The localization of HDACs known from studies using neuronal cells, the lethality in total knockout mice and the neuronal phenotypes in loss-of-function mutant is indicated.

Figure 2

Figure 2. The roles of HDACs in neuron development

The differentiation of neuronal progenitor cells to neurons requires the transduction of signals to the genome to de-repress neuron-specific genes. The nuclear export of HDAC3, HDAC5 and HDAC9 induces neurogenesis and differentiation by activating target genes. HDAC1 and HDAC2 are required for this process as well, in part by silencing progenitor transcripts and by promoting the expression of a neurogenic program. The development of axon and dendrites also depends upon HDACs function. In addition to a traditional role of HDACs in regulating gene expression, HDACs also influence dendrite and axon development through their action on the cytoskeleton (HDAC6) and signaling pathways (Sirt1).

Figure 3

Figure 3. The roles of HDACs in axon regeneration

Axon injury triggers multiple events that engage several HDACs locally at the site of injury as well as distantly in the cell soma. In the injured axon, HDAC5 and HDAC6 regulate the necessary changes in the microtubule cytoskeleton to optimize growth cone dynamics and axon re-growth. Whereas HDAC5 activity is required for re-growth on permissive substrates, HDAC6 prevents growth on inhibitory substrates mimicking the environment of the injured CNS. In the cell soma, injury-induced nuclear export of HDAC5 and HDAC3 elicits changes in the epigenetic landscape that are required to activate a pro-regenerative gene expression program.

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