Silencing of microRNAs in vivo with ‘antagomirs’

Jan Krützfeldt, Nikolaus Rajewsky, Ravi Braich, Kallanthottathil G. Rajeev, Thomas Tuschl, Muthiah Manoharan and Markus Stoffel ()
Additional contact information
Jan Krützfeldt: The Rockefeller University
Nikolaus Rajewsky: New York University
Ravi Braich: Alnylam Pharmaceuticals Inc.
Kallanthottathil G. Rajeev: Alnylam Pharmaceuticals Inc.
Thomas Tuschl: The Rockefeller University
Muthiah Manoharan: Alnylam Pharmaceuticals Inc.
Markus Stoffel: The Rockefeller University

Nature, 2005, vol. 438, issue 7068, 685-689

Abstract: miRNAs acting naturally The discovery of microRNAs (miRNAs), the non-coding RNAs thought to be involved in many biological processes, is changing our perception of gene regulation. Little is known about their function in mammalian systems in vivo, but a newly developed group of compounds that silences miRNAs in mice should provide a powerful tool for the study of their function — and a potential therapeutic strategy for silencing miRNAs in disease. These ‘antagomirs’ are chemically engineered oligonucleotides with sequences that complement natural miRNAs. Intravenous administration of antagomirs to miR-16, -122, -192 and -194 in mice caused a marked reduction of corresponding miRNA expression in liver, lung, kidney, heart, muscle, intestine, fat, skin, bone marrow, ovaries and adrenals. In worms and flies, miRNAs play important developmental roles in the embryo. In vertebrates, various developmental genes have been shown to be targets of miRNA regulation, but there were no examples of miRNAs playing specific roles in known developmental processes. Now one such example has been found: miR-196 acts in mouse embryos as a mechanism to ensure accurate expression of genes primarily regulated by Hoxb8 and Shh transcription factors. This supports the idea that vertebrate miRNAs may function as a secondary level of gene regulation.

Date: 2005
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DOI: 10.1038/nature04303

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