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MicroRNAs with macro effects

The Journal of Cell Biology
The Rockefeller University Press
Publication Date
DOI: 10.1083/jcb.1774rr5
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JCB_1774rr.indd Research Roundup JCB • VOLUME 177 • NUMBER 4 • 2007568 MicroRNAs with macro effects T he fi rst microRNA (miRNA) knock-out mice reveal that these tiny RNAs have sizeable power over mammalian physiology, as shown by three new reports. Rather than coding for proteins, miRNAs decrease protein levels by bind- ing to their mRNA targets. Since their discovery in worms, researchers have wondered whether miRNAs simply fi ne- tune the genome’s work or have large- scale effects of their own. The fi rst reports of mice lacking specifi c miRNAs suggest their effects are wide and strong. Antony Rodriguez, Allan Bradley (Sanger Institute, London, UK), and colleagues knocked out the gene coding for miR-155, which is active in the immune system and is up-regulated in lymphomas. The mice had defective T cell responses, were unable to fi ght off infec- tion, and displayed lung tissue scarring seen in autoimmune diseases. The same miRNA was also deleted by To-Ha Thai, Klaus Rajewsky (Harvard Medical School, Boston, MA), and col- leagues. They found that these mice also had B cell defects. In normal animals, antigen-activated B cells proliferate in the germinal centers (GCs), which generate high-affi nity antibodies and control immune memory. But these GC reactions were blunted in the knockouts, whose B cells failed to produce the necessary cytokines. Overexpressing miR-155, in contrast, enhanced the GC reaction. Moving out of immunity and into the heart, Yong Zhao, Deepak Srivastava (Gladstone Institutes and University of California, San Francisco, CA), and colleagues knocked out miR-1-2, a reg- ulator of cardiogenesis. The gene is one of two that encode identical mature miRNAs, yet even just cutting total miR-1 levels in half produced errors in cell cycle regulation and electroconduc- tance in heart cells. The group found that the target mRNA’s secondary struc- ture must be open enough for the miRNA to attach. “If you imagine the mRNA balled

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