Nucleocytoplasmic Shuttling of Histone Deacetylase 9 Controls Activity-Dependent Thalamocortical Axon Branching

Alchini, Ricardo; Sato, Haruka; Matsumoto, Naoyuki; Shimogori, Tomomi; Sugo, Noriyuki; Yamamoto, Naoya

doi:10.1038/s41598-017-06243-7

Cited by 11 publications

(8 citation statements)

References 61 publications

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“…As class IIa HDACs and ERGs are expressed throughout the brain and in various neuron types, including GABAergic interneurons 4,25,30,41,60 , it is possible that transcriptional mechanisms described here broadly regulate neural circuits and behavior. It is also noteworthy that vertebrate genomes have two other class II HDAC isoforms whose roles in the nervous system remain unclear: HDAC7, which appears to be predominantly expressed during early development, and HDAC9, which encodes a short protein that lacks the C-terminal deacetylase domain but also interacts with MEF2 20,25,67 .…”

Section: Discussionmentioning

confidence: 99%

Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription

et al. 2019

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The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of information coding remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of transcriptional programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage.

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Section: Discussionmentioning

confidence: 99%

Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription

et al. 2019

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“…These findings are fully consistent with previous reports showing that axon injury in peripheral sensory neurons resulted in nuclear export of HDAC5, which promoted axon regeneration both in vitro and in vivo (Cho et al, 2013). Moreover, previous studies have implicated HDAC9 as a negative regulator of reinnervation of mouse skeletal muscle (Macpherson et al, 2015), and shown that nucleo-cytoplasmic translocation of HDAC9 plays a critical role in activity-dependent thalamocortical axon branching (Alchini et al, 2017), showing that a cytoplasmic localization of HDAC5 promotes neurite growth. Immunohistochemical staining of the adult mouse SN confirmed a predominantly cytoplasmic localization for HDAC5 and HDAC9, suggesting that this may create a permissive environment for dopaminergic axon maintenance in adulthood.…”

Section: Discussionmentioning

confidence: 99%

“…In agreement with this, the class-IIa HDAC inhibitor MC1568 (Mai et al, 2005), was found to promote neurite growth in mDA neurons, and to protect against the neuritotoxic effects of MPP + (Collins et al, 2015). Nuclear export of HDAC5 and HDAC9 has also been shown to be required for axonal growth in sensory neurons (Cho et al, 2013) and thalamocortical neurons (Alchini et al, 2017). However, whether class-IIa HDACs can be targeted to promote neurite growth in cells carrying α-synuclein, the mechanisms mediating these potential effects, and the relevance of this to the human midbrain, are unknown.…”

Section: Introductionmentioning

confidence: 99%

Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling

Mazzocchi

Wyatt

Mercatelli

et al. 2019

Front. Cell Dev. Biol.

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Parkinson’s disease is characterized by the intracellular accumulation of α-synuclein which has been linked to early dopaminergic axonal degeneration. Identifying druggable targets that can promote axonal growth in cells overexpressing α-synuclein is important in order to develop strategies for early intervention. Class-IIa histone deacetylases (HDACs) have previously emerged as druggable targets, however, it is not known which specific class-IIa HDACs should be targeted to promote neurite growth in dopaminergic neurons. To provide insight into this, we used gene co-expression analysis to identify which, if any, of the class-IIa HDACs had a positive correlation with markers of dopaminergic neurons in the human substantia nigra. This revealed that two histone deacetylases, HDAC5 and HDAC9, are co-expressed with TH, GIRK2 and ALDH1A1 in the human SN. We further found that HDAC5 and HDAC9 are expressed in dopaminergic neurons in the adult mouse substantia nigra. We show that siRNAs targeting HDAC5 or HDAC9 can promote neurite growth in SH-SY5Y cells, and that their pharmacological inhibition, using the drug MC1568, promoted neurite growth in cultured rat dopaminergic neurons. Moreover, MC1568 treatment upregulated the expression of the neurotrophic factor, BMP2, and its downstream transcription factor, SMAD1. In addition, MC1568 or siRNAs targeting HDAC5 or HDAC9 led to an increase in Smad-dependent GFP expression in a reporter assay. Furthermore, MC1568 treatment of cultured rat dopaminergic neurons increased cellular levels of phosphorylated Smad1, which was prevented by the BMP receptor inhibitor, dorsomorphin. Dorsomorphin treatment prevented the neurite growth-promoting effects of siRNAs targeting HDAC5, as did overexpression of dominant-negative Smad4 or of the inhibitory Smad7, demonstrating a functional link to BMP signaling. Supplementation with BMP2 prevented the neurite growth-inhibitory effects of nuclear-restricted HDAC5. Finally, we report that siRNAs targeting HDAC5 or HDAC9 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein and that MC1568 protected cultured rat dopaminergic neurons against the neurotoxin, MPP+. These findings establish HDAC5 and HDAC9 as novel regulators of BMP-Smad signaling, that additionally may be therapeutic targets worthy of further exploration in iPSC-derived human DA neurons and in vivo models of Parkinson’s disease.

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“…Similarly, another study reported that nuclear export of HDAC9 is required for axonal branching in thalamocortical neurons [ 46 ]. Specifically, this study showed that nuclear export of HDAC9 occurs during the process of thalamocortical axonal branching, and that overexpression of a form of HDAC9 that is retained in the nucleus resulted in inhibition of this branching [ 46 ]. In contrast with the above studies that showed detrimental effects of class II HDACs on neurons, HDAC7 expression has been found to protect cerebellar granule neurons from apoptosis through a deacetylase-independent mechanism [ 47 ].…”

Section: Class Iia Hdacs As Therapeutic Targets For Pdmentioning

confidence: 97%

“…Moreover, injury-induced nuclear export of HDAC5 has been shown to be required for axonal regeneration in peripheral sensory neurons, since localisation of HDAC5 exclusively to the nucleus prevented axonal regeneration [45]. Similarly, another study reported that nuclear export of HDAC9 is required for axonal branching in thalamocortical neurons [46]. Specifically, this study showed that nuclear export of HDAC9 occurs during the process of thalamocortical axonal branching, and that overexpression of a form of HDAC9 that is retained in the nucleus resulted in inhibition of this branching [46].…”

Section: Class Iia Hdacs As Therapeutic Targets For Pdmentioning

confidence: 98%

The class II histone deacetylases as therapeutic targets for Parkinson’s disease

et al. 2020

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by specific motor impairments. The neuropathological hallmarks of PD include progressive degeneration of midbrain dopaminergic neurons, and loss of their axonal projections to the striatum. Additionally, there is progressive accumulation and spread of intracellular aggregates of α-synuclein. Although dopamine-replacement pharmacotherapy can treat PD symptoms in the short-term, there is a critical need for the development of disease-modifying therapies based on an understanding of the underlying disease mechanisms. One such mechanism is histone acetylation, which is a common epigenetic modification that alters gene transcription. A number of studies have described alterations in histone acetylation in the brains of PD patients. Moreover, α-synuclein accumulation has been linked to alterations in histone acetylation and pharmacological strategies aimed at modulating histone acetylation are under investigation as novel approaches to disease modification in PD. Currently, such strategies are focused predominantly on pan-inhibition of histone deacetylase (HDAC) enzymes. Inhibition of specific individual HDAC enzymes is a more targeted strategy that may allow for future clinical translation. However, the most appropriate class of HDACs that should be targeted for neuroprotection in PD is still unclear. Recent work has shed new light on the role of class-II HDACs in dopaminergic degeneration. For this reason, here we describe the regulation of histone acetylation, outline the evidence for alterations in histone acetylation in the PD brain, and focus on the roles of class II HDACs and the potential of class-II HDAC inhibition as a therapeutic approach for neuroprotection in PD.

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Nucleocytoplasmic Shuttling of Histone Deacetylase 9 Controls Activity-Dependent Thalamocortical Axon Branching

Cited by 11 publications

References 61 publications

Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription

Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription

Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling

The class II histone deacetylases as therapeutic targets for Parkinson’s disease

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