A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.

Autophagy
Liam D CassidyMasashi Narita

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.

References

Nov 5, 2004·Nature·Akiko KumaNoboru Mizushima
May 4, 2005·The Journal of Cell Biology·Masaaki KomatsuTomoki Chiba
Jan 10, 2006·Genesis : the Journal of Genetics and Development·Caroline BeardRudolf Jaenisch
Feb 18, 2009·The Journal of Clinical Investigation·Anurag Kumar SinghUrsula Seidler
Mar 13, 2009·Genes & Development·Andrew R J YoungMasashi Narita
Dec 1, 2009·Cell Metabolism·Eva MasieroMarco Sandri
Sep 3, 2010·Nature Cell Biology·Noboru Mizushima, Beth Levine
Apr 19, 2011·Genes & Development·Akito TakamuraNoboru Mizushima
Aug 2, 2011·Journal of Hepatology·Lien F R ThoenLeo A van Grunsven
Feb 4, 2012·Nature Protocols·Lukas E DowScott W Lowe
Sep 1, 2012·Nature Reviews. Drug Discovery·David C RubinszteinBeth Levine
Dec 7, 2013·Nature·Mathias T RosenfeldtKevin M Ryan
Dec 18, 2013·Cell Reports·Christof FellmannJohannes Zuber
May 31, 2014·Cancer Discovery·Gizem Karsli-UzunbasEileen White
Jul 31, 2014·Proceedings of the National Academy of Sciences of the United States of America·Keiko IwaisakoTatiana Kisseleva
Feb 6, 2015·The Journal of Clinical Investigation·Guido Kroemer
Feb 6, 2015·The Journal of Clinical Investigation·Beth LevinePatrice Codogno
Feb 6, 2015·The Journal of Clinical Investigation·Eileen White
May 21, 2015·Nature Reviews. Neuroscience·Fiona M MenziesDavid C Rubinsztein
Jun 11, 2015·Autophagy·Jasper LodderFatima Teixeira-Clerc
Jan 8, 2016·Nature·Laura García-PratPura Muñoz-Cánoves
Aug 19, 2017·Autophagy·Akiko KumaNoboru Mizushima

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Citations

May 31, 2019·Current Opinion in Clinical Nutrition and Metabolic Care·Jeannette KönigChristiane Ott
Jan 18, 2020·Nature Communications·Liam D CassidyMasashi Narita
Oct 12, 2019·Cell Death & Disease·Friedemann LoosGuido Kroemer
Sep 19, 2020·Molecular & Cellular Oncology·Liam D Cassidy, Masashi Narita
Dec 11, 2020·Advanced Drug Delivery Reviews·Takahiro YamazakiFederico Pietrocola
Feb 4, 2019·Journal of Hepatology·Manon AllaireSophie Lotersztajn
Jun 15, 2021·Molecular Aspects of Medicine·Hui QianWen-Xing Ding
Aug 31, 2021·The EMBO Journal·Daniel J KlionskyFederico Pietrocola
Jan 6, 2022·Journal of Cellular and Molecular Medicine·Xiaoning YangFanghua Gong

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Methods Mentioned

BETA
Assay
FACS

Software Mentioned

Fiji
HALO TM
FlowJo

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