RNA interference (RNAi) has emerged as a fundamentally important biological phenomenon and as a versatile, powerful tool for biomedical research. In organisms from fungi and flies to plants and mammals, RNAi plays a multifaceted role in molecular biology by silencing genes through chromatin remodeling, interfering with protein synthesis, and--in its best-studied mode of action--quashing gene expression by cleaving messenger RNA. Experimental applications of RNAi have spurred the exploration of gene function in many basic research, drug discovery, and clinical settings. Until now, however, the identity of the molecular scissors that carry out RNAi-mediated messenger RNA cleavage has not been revealed.

Two studies published this week in Science have resolved this mystery by establishing that Argonaute2, a signature protein component of the RNA interference machinery, provides the cutting action that carries out RNAi-mediated messenger RNA cleavage. The studies were conducted at Cold Spring Harbor Laboratory by research groups led by Greg Hannon and Leemor Joshua-Tor.

Hannon's group focused on sorting out the functions of four mammalian Argonaute family members (Ago1, 2, 3, and 4). First, through a biochemical approach, Hannon and his colleagues found that only a single Argonaute family member, Ago2, supports the formation of mRNA cleavage-competent complexes in vitro.

To extend these biochemical findings to an in vivo setting, and to further explore the specialization of Argonaute family member function, Hannon's group disrupted the mouse Ago2 gene by targeted insertional mutagenesis. The researchers observed an embryonic lethal phenotype and striking developmental abnormalities in Ago2 homozygotes.

All Ago2 homozygous embryos displayed defects in neural tube structure, with half of the embryos showing complete failure of neural tube closure in the head region. The embryos also had enlarged hearts and pronounced swelling of the
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Contact: Peter Sherwood
sherwood@cshl.edu
516-367-6947
Cold Spring Harbor Laboratory
29-Jul-2004

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