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RESEARCH COMMUNICATION

A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway

¹ The Laboratory for Lymphocyte Signaling, The Rockefeller University, New York, New York 10021, USA; ² Wellcome Trust/Cancer Research, UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, United Kingdom; ³ Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom

Binding of microRNA (miRNA) to mRNA within the RNA-induced silencing complex (RISC) leads to either translational inhibition or to destruction of the target mRNA. Both of these functions are executed by Argonaute 2 (Ago2). Using hematopoiesis in mice as a model system to study the physiological function of Ago2 in vivo, we found that Ago2 controls early development of lymphoid and erythroid cells. We show that the unique and defining feature of Ago2, the Slicer endonuclease activity, is dispensable for hematopoiesis. Instead, we identified Ago2 as a key regulator of miRNA homeostasis. Deficiency in Ago2 impairs miRNA biogenesis from precursor-miRNAs followed by a reduction in miRNA expression levels. Collectively, our data identify Ago2 as a highly specialized member of the Argonaute family with an essential nonredundant Slicer-independent function within the mammalian miRNA pathway.

[Keywords: Ago2; Slicer; microRNA; hematopoeisis]

Received April 30, 2007; revised version accepted June 5, 2007.

⁵ Corresponding authors.

E-MAIL donal.ocarroll{at}embl-monterotondo.it; FAX 39-060900-91406.

⁶ E-MAIL tarakho{at}mail.rockefeller.edu; FAX (212) 327-8258.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1565607

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