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ON-bipolar cell gene expression during retinal degeneration: Implications for optogenetic visual restoration.

Gilhooley, MJ; Hickey, D; Lindner, M; Palumaa, T; Hughes, S; Peirson, SN; MacLaren, RE; (2021) ON-bipolar cell gene expression during retinal degeneration: Implications for optogenetic visual restoration. Experimental Eye Research , Article 108553. 10.1016/j.exer.2021.108553. (In press). Green open access

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Abstract

PURPOSE: Retinal bipolar cells survive even in the later stages of inherited retinal degenerations (IRDs) and so are attractive targets for optogenetic approaches to vision restoration. However, it is not known to what extent the remodelling that these cells undergo during degeneration affects their function. Specifically, it is unclear if they are free from metabolic stress, receptive to adeno-associated viral vectors, suitable for opsin-based optogenetic tools and able to propagate signals by releasing neurotransmitter. METHODS: Fluorescence activated cell sorting (FACS) was performed to isolate labelled bipolar cells from dissociated retinae of litter-mates with or without the IRD mutation Pde6brd1/rd1 selectively expressing an enhanced yellow fluorescent protein (EYFP) as a marker in ON-bipolar cells. Subsequent mRNA extraction allowed Illumina® microarray comparison of gene expression in bipolar cells from degenerate to those of wildtype retinae. Changes in four candidate genes were further investigated at the protein level using retinal immunohistochemistry over the course of degeneration. RESULTS: A total of sixty differentially expressed transcripts reached statistical significance: these did not include any genes directly associated with native primary bipolar cell signalling, nor changes consistent with metabolic stress. Four significantly altered genes (Srm2, Slf2, Anxa7 & Cntn1), implicated in synaptic remodelling, neurotransmitter release and viral vector entry had immunohistochemical staining colocalising with ON-bipolar cell markers and varying over the course of degeneration. CONCLUSION: Our findings suggest relatively few gene expression changes in the context of degeneration: that despite remodelling, bipolar cells are likely to remain viable targets for optogenetic vision restoration. In addition, several genes where changes were seen could provide a basis for investigations to enhance the efficacy of optogenetic therapies.

Type: Article
Title: ON-bipolar cell gene expression during retinal degeneration: Implications for optogenetic visual restoration.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.exer.2021.108553
Publisher version: https://doi.org/10.1016/j.exer.2021.108553
Language: English
Additional information: This work is licensed under a CC BY License.
Keywords: Bipolar cell, Gene expression, Inherited retinal degeneration, Optogenetics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10125754
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