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Researchers achieve germline transmission of ’gene knockdown’ in mice


RNA interference (RNAi) has emerged as an extremely versatile and powerful tool in biomedical research. A new study published in the February issue of Nature Structural Biology reports the creation of transgenic mice in which inherited RNAi lowers or silences the expression of a target gene, producing a stable "gene knockdown." This finding extends the power of RNAi to genetic studies in live animals, and has far-reaching implications for the study and treatment of many human diseases.

To adapt RNAi for the study of gene function in mice, Thomas Rosenquist of Stony Brook University (; tel: 631-444-8054) and Greg Hannon of Cold Spring Harbor Laboratory (; tel: 516-367-8889) used genetic engineering to create mouse embryonic stem cells in which RNAi was targeted to a particular gene. (As Hannon and his colleagues established in a previous study, silencing a gene of interest through RNAi can be efficiently achieved by engineering a second gene that encodes short hairpin RNA molecules corresponding to the gene of interest.)

These stem cells were injected into mouse embryos, and chimeric animals were born. Matings of these chimeric mice produced offspring that contained the genetically engineered RNAi-inducing gene in every cell of their bodies.

When Rosenquist, Hannon, and their colleagues examined tissues from the transgenic mice, they found that expression of the gene of interest was significantly reduced everywhere they looked (e.g. liver, heart, spleen). Such a reduction in gene expression is called a "gene knockdown" to distinguish it from traditional methods that involve "gene knockouts" or the complete deletion of a DNA segment from a chromosome.

One advantage of the RNAi-based gene knockdown strategy, shown in this study to work in whole animals, is that in future incarnations, the strategy can be modified to silence the expression of genes in specific tissues, and it can be designed to be switched on and off at any time during the development or adulthood of the animal. These and other features of the strategy, as well as combining it with drug discovery and other methods, should enable scientists to uncover a great deal of information about how genes influence many normal and pathological processes.

Although the current study targeted a gene thought to be involved in DNA repair, any gene would have sufficed as a target to demonstrate proof of principle as this study has done.

The creation of germline transgenic mice with heritable RNAi opens the door to the manipulation of gene activity in living animals for many applications.

Peter Sherwood | EurekAlert!
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