Transcriptional profiling of the rat retina after optic nerve crush uncovers sustained activation of the complement cascade and Delta-Notch signaling pathways

Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the neurons known as retinal ganglion cells (RGCs). Although distinct in vivo animal models have been used to investigate the mechanisms of both RGC degeneration and reorganization of the retina, there has been little progress in developing efficient strategies for neuroprotection in glaucoma. In the present study, we used transcriptomic profiles of Lister Hooded rats’ retinas 2 weeks after optic nerve crush (ONC) and applied systems biology approaches to better understand the molecular mechanisms by which ONC induced the remodeling of the retinal tissue. We calculated the relative expression variability scored as a statistical measure of the variability of transcript abundance in our datasets and found higher variability after ONC. Also, gene expression stability was used as a score of transcription control and we found a reduction in the number of very stably expressed genes from 336 to 124. Enrichment analysis showed that Complement cascade and Notch signaling pathway were the main affected pathways after ONC. In order to deepen our studies on these two pathways, we performed coordination analysis of genes within each pathway and with the entire transcriptome. ONC increased the number of synergistically coordinated pairs of genes and increased the number of similar profiles. This study goes beyond the regulation of individual gene expression showing striking changes in the control of expression by Complement cascade and Notch signaling functional pathways important for RGC degeneration and remodeling of the retinal tissue two weeks after ONC. One tissue (retina) x one sex (female) x two conditions (ONC = intraorbital optic nerve crush, CTR = control sham operated)