A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.
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Authors
Pérez-Mancera, Pedro A
Jaulim, Sheik
Brais, Rebecca
Ricketts, Thomas
Publication Date
2018Journal Title
Autophagy
ISSN
1554-8627
Publisher
Informa UK Limited
Volume
14
Issue
7
Pages
1256-1266
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Cassidy, L. D., Young, A., Pérez-Mancera, P. A., Nimmervoll, B., Jaulim, S., Chen, H., McIntyre, D., et al. (2018). A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.. Autophagy, 14 (7), 1256-1266. https://doi.org/10.1080/15548627.2018.1458172
Abstract
Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts. We show that ATG5i mice recapitulate many of the previously described phenotypes of tissue-specific knockouts. While restoration of autophagy in the liver rescues hepatomegaly and other pathologies associated with autophagy deficiency, this coincides with the development of hepatic fibrosis. These results highlight the need to consider the potential side effects of systemic anti-autophagy therapies.
Keywords
Animals, Animals, Newborn, Liver Cirrhosis, RNA, Small Interfering, Models, Animal, Down-Regulation, Phenotype, Time Factors, Autophagy, Autophagy-Related Protein 5
Sponsorship
Cancer Research UK (C14303/A17197)
Wellcome Trust (095317/Z/11/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (107609/Z/15/Z)
Cancer Research UK (C20/A20976)
Medical Research Council (MR/M013049/1)
Cancer Research UK (CB4210)
Medical Research Council (MR/R010013/1)
Medical Research Council (MC_UU_12012/5)
National Cancer Institute (P01CA096832)
Identifiers
External DOI: https://doi.org/10.1080/15548627.2018.1458172
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273231
Rights
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http://www.rioxx.net/licenses/all-rights-reserved
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