Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

Retinal Genomic Fabrics Remodeling after Optic Nerve Injury

Version 1 : Received: 31 March 2020 / Approved: 2 April 2020 / Online: 2 April 2020 (11:59:28 CEST)
Version 2 : Received: 19 February 2021 / Approved: 23 February 2021 / Online: 23 February 2021 (12:44:20 CET)

How to cite: Victorino, P.H.; Marra, C.; Iacobas, D.A.; Iacobas, S.; Spray, D.C.; Linden, R.; Adesse, D.; Petrs-Silva, H. Retinal Genomic Fabrics Remodeling after Optic Nerve Injury. Preprints 2020, 2020040016 (doi: 10.20944/preprints202004.0016.v2). Victorino, P.H.; Marra, C.; Iacobas, D.A.; Iacobas, S.; Spray, D.C.; Linden, R.; Adesse, D.; Petrs-Silva, H. Retinal Genomic Fabrics Remodeling after Optic Nerve Injury. Preprints 2020, 2020040016 (doi: 10.20944/preprints202004.0016.v2).

Abstract

Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the Genomic Fabric Paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers for the expression of each gene 3 independent characteristics: level, variability and correlation with each other gene. Thus, the 17,657 quantified genes our study generated a total of 155,911,310 values to analyze. This represents 8,830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with DiI. We observed a higher Relative Expression Variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted Protein-Protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among up-regulated genes. Enrichment analysis showed that Complement Cascade and Notch Signaling Pathway, as well as Oxidative Stress and Kit Receptor Pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pair-wise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in Complement Cascade and Notch Signaling Pathway. This deep bioinformatic study provides novel insights beyond the regulation of individual gene expression and discloses changes in the control of expression of Complement Cascade and Notch Signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.

Subject Areas

glaucoma; retina ganglion cell degeneration; microarray; genes coordination; notch signaling pathway; complement cascade

Comments (1)

Comment 1
Received: 23 February 2021
Commenter: Daniel Adesse
Commenter's Conflict of Interests: Author
Comment: This manuscript underwent 5 revision rounds and referees requested additional RT-PCR validations and re-writing of several parts of the text.
+ Respond to this comment

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 1
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.