Genetic Networks in Mouse Retinal Ganglion Cells

Abstract

Retinal ganglion cells (RGCs) are the output neuron of the eye, transmitting visual information from the retina through the optic nerve to the brain. The importance of RGCs for vision is demonstrated in blinding diseases where RGCs are lost, such as in glaucoma or after optic nerve injury. In the present study, we hypothesize that normal RGC function is transcriptionally regulated. To test our hypothesis, we examine large retinal expression microarray datasets from recombinant inbred mouse strains in GeneNetwork and define transcriptional networks of RGCs and their subtypes. Two major and functionally distinct transcriptional networks centering around Thy1 and Tubb3 (Class III beta-tubulin) were identified. Each network is independently regulated and modulated by unique genomic loci. Meta-analysis of publically available data confirms that RGC subtypes are differentially susceptible to death, with alpha-RGCs and intrinsically photosensitive RGCs (ipRGCs) being less sensitive to cell death than other RGC subtypes in a mouse model of glaucoma.

Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse

“…An interesting possibility for the difference in axon loss we have demonstrated in the BXD strain set is differential susceptibility of RGC subtypes to IOP elevation. It was previously shown that alpha-RGCs and melanopsin-containing RGCs were more resistant to axotomy-induced cell death (Duan et al, 2015; Struebing et al, 2016), and similar observations were made in a mouse model of chronically elevated IOP (Feng et al, 2013). These findings argue for the existence of distinct transcriptional programs within each RGC subtype (Struebing et al, 2016).…”

“…It was previously shown that alpha-RGCs and melanopsin-containing RGCs were more resistant to axotomy-induced cell death (Duan et al, 2015; Struebing et al, 2016), and similar observations were made in a mouse model of chronically elevated IOP (Feng et al, 2013). These findings argue for the existence of distinct transcriptional programs within each RGC subtype (Struebing et al, 2016). Further developments in this area of research will certainly shed more light onto the molecular mechanisms leading to differential susceptibility of RGCs to death.…”

“…Because the high BXD genotyping density with > 17,000 segregating markers allows us to map with a precision of roughly ± 1 Mb, we examined the region on chromosome 18 from 53.6 to 57 Mb to define potential candidate genes modulating axonal loss. Good candidates should either contain nonsynonymous SNPs altering their amino acid sequence, or they should be cis-eQTLs, meaning that their expression level segregates into two groups defined by the distribution of parental alleles (Struebing et al, 2016). Examining the sequences between B6 and D2 using the SNP browser on GeneNetwork did not reveal genes with nonsynonymous SNPs within this 2 Mb large region.…”

“…6). While TUJ1 is known to stain RGCs and a few other retinal neurons as well as axons, RBPMS expression was shown to be restricted to the RGC population (Rodriguez et al, 2014; Struebing et al, 2016). ALDH7A1 co-localized with all TUJ1-and RBPMS-positive cells, while ALDH7A1 staining was also present throughout other retinal layers, including cone photoreceptors.…”

POU6F2 Positive Retinal Ganglion Cells a Novel Group of ON-OFF Directionally Selective Subtypes in the Mouse Retina

“…POU6F2 was first described as a novel POU-domain transcription factor in the retina 24 and it identified a subpopulation of RGCs 24 . We have independently confirmed these findings and found that Pou6f2 is part of a genetic network found in mouse RGCs 25 . The first hint of the link between Pou6f2 modulating CCT in the mouse and its potential role in glaucoma is revealed during the development of the eye.…”