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Gain and loss-of-function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.<\/jats:p>","DOI":"10.7554\/elife.70948","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T08:01:03Z","timestamp":1630396863000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.70948","source":"Crossref","is-referenced-by-count":40,"title":["Inducible and reversible inhibition of miRNA-mediated gene repression in vivo"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1277-0566","authenticated-orcid":true,"given":"Gaspare","family":"La Rocca","sequence":"first","affiliation":[{"name":"Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center","place":["New York, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"King","sequence":"first","affiliation":[{"name":"Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center","place":["New York, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5956-130X","authenticated-orcid":true,"given":"Bing","family":"Shui","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana Farber Cancer Institute","place":["Boston, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Li","sequence":"additional","affiliation":[{"name":"Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center","place":["New York, United States"]},{"name":"Louis V. 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