The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess the effects of splicing regulatory compounds in vivo
dc.contributor.author | Stevens, M | |
dc.contributor.author | Star, E | |
dc.contributor.author | Lee, M | |
dc.contributor.author | Innes, E | |
dc.contributor.author | Li, L | |
dc.contributor.author | Bowler, E | |
dc.contributor.author | Harper, S | |
dc.contributor.author | Bates, DO | |
dc.contributor.author | Oltean, S | |
dc.date.accessioned | 2019-08-28T14:07:09Z | |
dc.date.issued | 2019-08-21 | |
dc.description.abstract | Vascular endothelial growth factor (VEGF)-A is differentially spliced to give two functionally different isoform families; pro-angiogenic, pro-permeability VEGF-Axxx and anti-angiogenic, anti-permeability VEGF-Axxxb. VEGF-A splicing is dysregulated in several pathologies, including cancer, diabetes, and peripheral arterial disease. The bichromatic VEGF-A splicing-sensitive fluorescent reporter harboured in a transgenic mouse is a novel approach to investigate the splicing patterns of VEGF-A in vivo. We generated a transgenic mouse harbouring a splicing-sensitive fluorescent reporter designed to mimic VEGF-A terminal exon splicing (VEGF8ab) by insertion into the ROSA26 genomic locus. dsRED expression denotes proximal splice site selection (VEGF-Axxx) and eGFP expression denotes distal splice site selection (VEGF-Axxxb). We investigated the tissue-specific expression patterns in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, and determined whether the splicing pattern could be manipulated in the same manner as endogenous VEGF-A by treatment with the SRPK1 inhibitor SPHINX 31. We confirmed expression of both dsRED and eGFP in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, with the highest expression of both fluorescent proteins observed in the exocrine pancreas. The ratio of dsRED and eGFP matched that of endogenous VEGF-Axxx and VEGF-Axxxb. Treatment of the VEGF8ab mice with SPHINX 31 increased the mRNA and protein eGFP/dsRED ratio in the exocrine pancreas, mimicking endogenous VEGF-A splicing. The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess splicing regulation in the individual cell-types and tissues, which provides a useful screening process for potentially therapeutic splicing regulatory compounds in vivo. | en_GB |
dc.description.sponsorship | BBSRC | en_GB |
dc.description.sponsorship | British Heart Foundation | en_GB |
dc.description.sponsorship | Diabetes UK | en_GB |
dc.identifier.citation | Published online 21 Aug 2019 | en_GB |
dc.identifier.doi | 10.1080/15476286.2019.1652522 | |
dc.identifier.grantnumber | BB/J007293/2 | en_GB |
dc.identifier.grantnumber | PG/15/53/31371 | en_GB |
dc.identifier.grantnumber | 17/0005668 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/38473 | |
dc.language.iso | en | en_GB |
dc.publisher | Taylor & Francis | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/31432737 | en_GB |
dc.rights | © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | en_GB |
dc.subject | Alternative splicing | en_GB |
dc.subject | angiogenesis | en_GB |
dc.subject | mouse model | en_GB |
dc.subject | splicing-sensitive fluorescent reporter | en_GB |
dc.subject | vascular endothelial growth factor-A | en_GB |
dc.title | The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess the effects of splicing regulatory compounds in vivo | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-08-28T14:07:09Z | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version. Available on open access from Taylor & Francis via the DOI in this record. | en_GB |
dc.identifier.journal | RNA Biology | en_GB |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2019-08-01 | |
exeter.funder | ::British Heart Foundation | en_GB |
exeter.funder | ::Diabetes UK | en_GB |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-08-21 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-08-28T13:56:06Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2019-10-18T08:29:30Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.