The microRNA miR-8 is a conserved negative regulator of Wnt signaling
- †Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048; and
- §Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622
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Communicated by Matthew P. Scott, Stanford University School of Medicine, Stanford, CA, August 6, 2008 (received for review March 19, 2008)
Abstract
Wnt signaling plays many important roles in animal development. This evolutionarily conserved signaling pathway is highly regulated at all levels. To identify regulators of the Wnt/Wingless (Wg) pathway, we performed a genetic screen in Drosophila. We identified the microRNA miR-8 as an inhibitor of Wg signaling. Expression of miR-8 potently antagonizes Wg signaling in vivo, in part by directly targeting wntless, a gene required for Wg secretion. In addition, miR-8 inhibits the pathway downstream of the Wg signal by repressing TCF protein levels. Another positive regulator of the pathway, CG32767, is also targeted by miR-8. Our data suggest that miR-8 potently antagonizes the Wg pathway at multiple levels, from secretion of the ligand to transcription of target genes. In addition, mammalian homologues of miR-8 promote adipogenesis of marrow stromal cells by inhibiting Wnt signaling. These findings indicate that miR-8 family members play an evolutionarily conserved role in regulating the Wnt signaling pathway.
Footnotes
- ¶To whom correspondence should be addressed. E-mail: cadigan{at}umich.edu
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Author contributions: J.A.K., I.G., O.A.M., and K.M.C. designed research; J.A.K. and I.G. performed research; J.A.K. contributed new reagents/analytic tools; J.A.K. and K.M.C. analyzed data; and J.A.K. and K.M.C. wrote the paper.
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↵‡Present address: Department of Biology, Vassar College, 124 Raymond Avenue, Poughkeepsie, NY 12604
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0807763105/DCSupplemental.
- © 2008 by The National Academy of Sciences of the USA
