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Erasing MicroRNAs Reveals Their Powerful Punch

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Science  27 Apr 2007:
Vol. 316, Issue 5824, pp. 530
DOI: 10.1126/science.316.5824.530

For more than 2 decades, biologists have illuminated the roles of genes by deleting them in mice and studying these “knockout” animals, which lack the proteins encoded by the targeted genes. Now, scientists say they're beginning to uncover an entirely new layer of gene regulation by using the same strategy to erase portions of genes that make snippets of RNA. Just as knockouts of traditional protein-coding genes yielded a treasure trove of knowledge about how different genes govern health and disease, this next generation of knockouts could fill in the gaps that remain.

In a flurry of papers, four independent groups have for the first time deleted mouse genes for microRNAs, RNA molecules that can modulate gene behavior. Each time, the rodents were profoundly affected, with some animals dropping dead of heart trouble and others suffering crippling immune defects.

Since their discovery more than a decade ago, microRNAs have electrified biologists. Geneticists estimate that the human body employs at least 500 during development and adult life. But it wasn't clear, especially in mammals, how important individual microRNAs were, because some evidence suggested that these gene-regulators had backups. In worms, for example, erasing a particular microRNA by deleting the relevant stretch of DNA occasionally had a dramatic effect but more often didn't appear to do much.

“I think there was a fear that nothing could be found” by deleting microRNA genes in mammals one at a time, says David Corry, an immunologist at Baylor College of Medicine in Houston, Texas. As it turns out, the opposite is true. “There's a lot more that the microRNAs are doing that we didn't appreciate until now,” says Frank Slack, a developmental biologist at Yale University who studies microRNAs in worms.

Two of the groups that produced the mammalian microRNA knockouts deleted the same sequence, for miR-155, and describe the effects on the mouse immune system on pages 604 and 608. One team was led by Allan Bradley at the Wellcome Trust Sanger Institute and Martin Turner of the Babraham Institute, both in Cambridge, U.K., and the other by Klaus Rajewsky of Harvard Medical School in Boston. The other teams, one whose results were published online by Science on 22 March ( and one whose work appears in the 20 April issue of Cell, eliminated different microRNAs and documented defects in mouse hearts.

The two groups that deleted miR-155 found that the rodents' T cells, B cells, and dendritic cells did not function properly, leaving the animals immunodeficient. The mutation also cut down the number of B cells in the gut, where the cells help fight infection, and triggered structural changes in the airways of the lungs, akin to what happens in asthma.

Missing molecules.

Compared to a normal mouse heart (top, left), one from a mouse with a deleted microRNA (top, right) overexpresses a skeletal muscle gene (in red), among other defects. Erasing a different microRNA increased collagen deposits (green) in mouse lungs (above, right) compared to a normal organ (above, left).


Still, left alone in a relatively sterile lab, mice lacking miR-155 survived easily. But when vaccinated against a strain of salmonella, the animals failed to develop protection against the bacterium—as quickly became apparent when most who were exposed to it died within a month. “The animals were no longer able to generate immunity,” says Turner, an immunologist.

Biologists typically see a specific defect when they knock out a protein-coding gene, but eliminating a microRNA may pack a bigger a punch, because many are thought to control multiple genes. In the case of miR-155, “you get much broader brush strokes … [and] very diverse immunological perturbations,” says Corry.

There's a flip side to the promiscuity of microRNAs: A single gene may be the target of many microRNAs. That led some biologists to speculate that built-in redundancy would limit damage caused by deleting individual microRNAs. In the Cell study in which miR-1-2 was deleted, the microRNA actually has an identical twin that's encoded by a gene on another chromosome. “We thought that we'd have to delete both of them to see any abnormality in the animal,” says Deepak Srivastava of the University of California, San Francisco, who led the work. But half of his group's mice died young of holes in the heart. Others later died suddenly, prompting Srivastava and his colleagues to look for, and find, heart rhythm disturbances.

The heart problems discovered by Eric Olson of the University of Texas Southwestern Medical Center in Dallas and his colleagues, which are also described on page 575, were more subtle. They erased the microRNA miR-208 and at first thought the mice were normal. Only when they subjected the animals to cardiac stress, by mimicking atherosclerosis and blocking thyroid signaling, did they observe that the animals' hearts reacted inappropriately to such strain.

The four teams that knocked out the various microRNAs still don't know all the gene targets of each molecule. The findings, says Turner, “really do leave open a lot more questions than perhaps there are answers.” One is whether these and other microRNAs help explain inherited defects in diseases for which genes have been elusive. Ailments from cancer to Alzheimer's disease, says Carlo Croce of Ohio State University in Columbus, who is studying microRNAs in malignancies, may “have a microRNA component.” It's one that scientists are beginning to hunt for in earnest.

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