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Transgene integration causes RARB downregulation in homozygous Tg4–42 mice

Alzheimer’s disease can be modelled by different transgenic mouse strains. To gain deeper insight into disease model mechanisms, the previously described Tg4–42 mouse was analysed for transgene integration. On RNA/DNA level the transgene integration resulted in more than 20 copy numbers and further...

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Autores principales: Hinteregger, Barbara, Loeffler, Tina, Flunkert, Stefanie, Neddens, Joerg, Birner-Gruenberger, Ruth, Bayer, Thomas A., Madl, Tobias, Hutter-Paier, Birgit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156671/
https://www.ncbi.nlm.nih.gov/pubmed/32286473
http://dx.doi.org/10.1038/s41598-020-63512-8
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author Hinteregger, Barbara
Loeffler, Tina
Flunkert, Stefanie
Neddens, Joerg
Birner-Gruenberger, Ruth
Bayer, Thomas A.
Madl, Tobias
Hutter-Paier, Birgit
author_facet Hinteregger, Barbara
Loeffler, Tina
Flunkert, Stefanie
Neddens, Joerg
Birner-Gruenberger, Ruth
Bayer, Thomas A.
Madl, Tobias
Hutter-Paier, Birgit
author_sort Hinteregger, Barbara
collection PubMed
description Alzheimer’s disease can be modelled by different transgenic mouse strains. To gain deeper insight into disease model mechanisms, the previously described Tg4–42 mouse was analysed for transgene integration. On RNA/DNA level the transgene integration resulted in more than 20 copy numbers and further caused a deletion of exon 2 of the retinoic acid receptor beta. These findings were also confirmed on protein level with highly decreased retinoic acid receptor beta protein levels in homozygous Tg4–42 mice and may have an impact on the previously described phenotype of homozygous Tg4–42 mice to be solely dependent on amyloid-ß 4–42 expression. Since hemizygous mice show no changes in RARB protein levels it can be concluded that the previously described phenotype of these mice should not be affected by the retinoic acid receptor beta gene knockout. In order to fully understand the results of transgenesis, it is extremely advisable to determine the genome integration site and the basic structure of the inserted transgenes. This can be carried out for instance by next-generation sequencing techniques. Our results thus suggest that a detailed characterization of new disease models using the latest genomics technologies prior to functional studies could be a valuable tool to avoid an unexpected genetic influence on the animals’ phenotype that is not only based on the inserted transgene. This would also significantly improve the selection of mouse models that are best suited for therapeutic development and basic research.
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spelling pubmed-71566712020-04-19 Transgene integration causes RARB downregulation in homozygous Tg4–42 mice Hinteregger, Barbara Loeffler, Tina Flunkert, Stefanie Neddens, Joerg Birner-Gruenberger, Ruth Bayer, Thomas A. Madl, Tobias Hutter-Paier, Birgit Sci Rep Article Alzheimer’s disease can be modelled by different transgenic mouse strains. To gain deeper insight into disease model mechanisms, the previously described Tg4–42 mouse was analysed for transgene integration. On RNA/DNA level the transgene integration resulted in more than 20 copy numbers and further caused a deletion of exon 2 of the retinoic acid receptor beta. These findings were also confirmed on protein level with highly decreased retinoic acid receptor beta protein levels in homozygous Tg4–42 mice and may have an impact on the previously described phenotype of homozygous Tg4–42 mice to be solely dependent on amyloid-ß 4–42 expression. Since hemizygous mice show no changes in RARB protein levels it can be concluded that the previously described phenotype of these mice should not be affected by the retinoic acid receptor beta gene knockout. In order to fully understand the results of transgenesis, it is extremely advisable to determine the genome integration site and the basic structure of the inserted transgenes. This can be carried out for instance by next-generation sequencing techniques. Our results thus suggest that a detailed characterization of new disease models using the latest genomics technologies prior to functional studies could be a valuable tool to avoid an unexpected genetic influence on the animals’ phenotype that is not only based on the inserted transgene. This would also significantly improve the selection of mouse models that are best suited for therapeutic development and basic research. Nature Publishing Group UK 2020-04-14 /pmc/articles/PMC7156671/ /pubmed/32286473 http://dx.doi.org/10.1038/s41598-020-63512-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hinteregger, Barbara
Loeffler, Tina
Flunkert, Stefanie
Neddens, Joerg
Birner-Gruenberger, Ruth
Bayer, Thomas A.
Madl, Tobias
Hutter-Paier, Birgit
Transgene integration causes RARB downregulation in homozygous Tg4–42 mice
title Transgene integration causes RARB downregulation in homozygous Tg4–42 mice
title_full Transgene integration causes RARB downregulation in homozygous Tg4–42 mice
title_fullStr Transgene integration causes RARB downregulation in homozygous Tg4–42 mice
title_full_unstemmed Transgene integration causes RARB downregulation in homozygous Tg4–42 mice
title_short Transgene integration causes RARB downregulation in homozygous Tg4–42 mice
title_sort transgene integration causes rarb downregulation in homozygous tg4–42 mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156671/
https://www.ncbi.nlm.nih.gov/pubmed/32286473
http://dx.doi.org/10.1038/s41598-020-63512-8
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