Abstract
BackgroundOptic nerve damage initiates a series of early atrophic events in retinal ganglion cells (RGCs) that precede the BAX-dependent committed step of the intrinsic apoptotic program. Nuclear atrophy, including global histone deacetylation, heterochromatin formation, shrinkage and collapse of nuclear structure, and the silencing of normal gene expression, comprise an important obstacle to overcome in therapeutic approaches to preserve neuronal function. Several studies have implicated histone deacetylases (HDACs) in the early stages of neuronal cell death, including RGCs. Importantly, these neurons exhibit nuclear translocation of HDAC3 shortly after optic nerve damage. Additionally, HDAC3 activity has been reported to be selectively toxic to neurons.ResultsRGC-specific conditional knockout of Hdac3 was achieved by transducing the RGCs of Hdac3fl/fl mice with an adeno-associated virus serotype 2 carrying CRE recombinase and GFP (AAV2-Cre/GFP). Controls included similar viral transduction of Rosa26fl/fl reporter mice. Optic nerve crush (ONC) was then performed on eyes. The ablation of Hdac3 in RGCs resulted in significant amelioration of characteristics of ONC-induced nuclear atrophy such as H4 deacetylation, heterochromatin formation, and the loss of nuclear structure. RGC death was also significantly reduced. Interestingly, loss of Hdac3 expression did not lead to protection against RGC-specific gene silencing after ONC, although this effect was achieved using the broad spectrum inhibitor, Trichostatin A.ConclusionAlthough other HDACs may be responsible for gene expression changes in RGCs, our results indicate a critical role for HDAC3 in nuclear atrophy in RGC apoptosis following axonal injury. This study provides a framework for studying the roles of other prevalent retinal HDACs in neuronal death as a result of axonal injury.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-39) contains supplementary material, which is available to authorized users.
Highlights
Optic nerve damage initiates a series of early atrophic events in retinal ganglion cells (RGCs) that precede the BAX-dependent committed step of the intrinsic apoptotic program
Gene silencing is not affected by Hdac3 Conditional knockout (cKO) retinas in RGCs post Optic nerve crush (ONC) Previously, we found that the use of the broad-spectrum histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), was effective in ameliorating RGCspecific Fem1c gene downregulation following ONC when administered intraperitoneally 24 hours prior to surgery
We demonstrated that H4 deacetylation and heterochromatin formation were prevented in RGCs of Hdac3 cKO retinas at 5 days following ONC
Summary
Optic nerve damage initiates a series of early atrophic events in retinal ganglion cells (RGCs) that precede the BAX-dependent committed step of the intrinsic apoptotic program. Baxdeficient RGCs remained viable up to at least 72 weeks post ONC, these cells exhibited many early stages of atrophy typical of wild type cells undergoing cell death [8]. This was evident in structural and functional changes in RGC nuclei. The RGC nuclei were found to exhibit atrophic characteristics including nuclear shrinkage, histone H4 deacetylation, heterochromatin formation, and RGC-specific gene silencing soon after ONC [8,10,16]
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