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Proteomics and transcriptomics analysis of rat retinal ganglion cells exposed to chronic ocular hypertension.

ABSTRACT: In this work, we tested feasibility of high content screening of acutely isolated RGCs to generate systems biology knowledge of intrinsic cellular pathways associated with the onset of glaucomatous RGC loss in the retina. We performed differential profiling of these neurons using two complementary techniques: proteomics and microarray-based transcriptomics. The analysis of these RGC-specific proteomic and transcriptomic data using pathway informatics databases and biological network tools have revealed complex metabolic and regulatory changes in the COH-challenged neurons. We used the iTRAQ reagents that allow for the identification and quantitation of up to four different samples simultaneously, to assess the COH-induced changes in protein content of adult rat RGCs. Similar principle is utilized in the two-color Agilent arrays that we used for our transcriptomic analysis of the same RGC samples.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE15332 | GEO | 2009/08/20

SECONDARY ACCESSION(S): PRJNA116561

REPOSITORIES: GEO

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Global gene expression changes in rat retinal ganglion cells after experimental glaucoma

Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma. The study was carried out in 3 adult male Brown Norway rats with experimental glaucoma. An equal number of RGCs were captured from normal eyes and eyes with elevated IOP. Gene expression in the glaucomatous RGC was compared with that in the fellow RGC by using Affymetrix Gene chip.

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NMNAT2 Is Downregulated in Glaucomatous RGCs and RGC-Specific Gene Therapy with NMNAT2 Overexpression Rescues Glaucomatous Neurodegeneration and Visual Function

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Global gene expression changes in rat retinal ganglion cells after experimental glaucoma

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Project description:The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury, but exacerbates the death of a subset of retinal ganglion cells, alpha-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent sumoylation at K91 increased nuclear localization and RGC differentiation in vitro. Here we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro, we found that non-SUMOylatable Sox11 K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11 K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in vivo in adult mouse. RNA-seq data showed that Sox11 and Sox11 K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated Spp1 and Opn4 expression in RGC cultures, consistent with negatively regulating the survival of α-RGCs and ipRGCs. Thus Sox11 and its sumoylation site at K91 regulate gene expression, survival and axon growth in RGCs and may be explored further as potential regenerative therapies for optic neuropathy.

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