Functional screening identifies miR-315 as a potent activator of Wingless signaling Journal Article
| Authors: | Silver, S. J.; Hagen, J. W.; Okamura, K.; Perrimon, N.; Lai, E. C. |
| Article Title: | Functional screening identifies miR-315 as a potent activator of Wingless signaling |
| Abstract: | The existence of vast regulatory networks mediated by microRNAs (miRNAs) suggests broad potential for miRNA dysfunction to contribute to disease. However, relatively few miRNA-target interactions are likely to make detectable contributions to phenotype, and effective strategies to identify these few interactions are currently wanting. We hypothesized that signaling cascades represent critical points of susceptibility to miRNA dysfunction, and we developed a strategy to test this theory by using quantitative cell-based screens. Here we report a screen for miRNAs that affect the Wingless (Wg) pathway, a conserved pathway that regulates growth and tissue specification. This process identified ectopic miR-315 as a potent and specific activator of Wg signaling, an activity that we corroborated in transgenic animals. This miR-315 activity was mediated by direct inhibition of Axin and Notum, which encode essential, negatively acting components of the Wg pathway. Genetic interaction tests substantiated both of these genes as key functional targets of miR-315. The ability of ectopic miR-315 to activate Wg signaling was not a trivial consequence of predicted miRNA-target relationships because other miRNAs with conserved sites in the Axin 3′ UTR neither activated Wg outputs nor inhibited an Axin sensor. In summary, activity-based screening can selectively identify miRNAs whose deregulation can lead to interpretable phenotypic consequences. © 2007 by The National Academy of Sciences of the USA. |
| Keywords: | signal transduction; controlled study; unclassified drug; proto-oncogene proteins; nonhuman; phenotype; animals; microrna; gene expression; drosophila; animalia; janus kinase; transgene; base sequence; 3' untranslated region; dna primers; micrornas; screening test; drosophila proteins; wnt1 protein; drosophila protein; axin; 3' untranslated regions; tissue specificity; stat protein; animals, genetically modified; mir 315; notum |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 104 |
| Issue: | 46 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2007-11-13 |
| Start Page: | 18151 |
| End Page: | 18156 |
| Language: | English |
| DOI: | 10.1073/pnas.0706673104 |
| PUBMED: | 17989227 |
| PROVIDER: | scopus |
| PMCID: | PMC2084312 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 18" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus" |
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