Endocrine Abstracts (2004) 7 S50

Mammalian RNA interference pathways

MT McManus & PA Sharp


Center for Cancer Research, Cambridge, MA, United States.


Now that the sequence of the entire human genome is known and the number of predicted genes is estimated, the next challenge is to assign biological function to each of the genes. A new and very powerful way for exploring gene function is offered by RNA interference (RNAi). In this method, the introduction of double-stranded RNA identical in sequence to that of the gene of interest inactivates the gene or, more precisely, 'interferes' with its function.

The discovery of small interfering RNAs (siRNAs) and microRNAs (miRNAs) has brought many surprises and questions to biology. While siRNAs exhibit perfect complementary to mRNAs and mediate RNAi, miRNAs are only partially complementary and act as translational regulators of gene expression in metazoans. The miRNA and RNAi pathways are fundamentally related as members of the Dicer and the Argonaute protein families are involved in both of these RNA-mediated silencing processes. We are using both computational approaches and mouse models to explore the roles of these pathways in mammalian cells.

One aspect of our work involves the study of transgenic mice where genes in the RNAi pathway have been disrupted or misexpressed. This includes the genes for Dicer, Argonaute, and miRNAs. Using these transgenics, we have discovered interesting intersections between the RNAi pathway and mammalian developmental processes. A second aspect of our work involves the innovation of tools that use the RNAi pathway to silence gene expression. These tools include conditional and lentiviral-based RNAi constructs that allow inducible RNAi to be performed in primary mouse tissues, opening up new approaches for dissecting gene function in mammals. These tools may one day be exploited for RNA-based therapeutics, but are currently proving to be incredibly useful for dissecting the function of thousands of genes present in eukaryotic genomes.

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