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Science 338 (6113): 1472-1476

Copyright © 2012 by the American Association for the Advancement of Science

A Steroid Receptor–MicroRNA Switch Regulates Life Span in Response to Signals from the Gonad

Yidong Shen1,2, Joshua Wollam1,2, Daniel Magner1,2, Oezlem Karalay1, and Adam Antebi1,2,3,*

1 Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, D-50931 Cologne, Germany.
2 Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
3 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50674 Cologne, Germany.

Figure 1
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Fig. 1. Ablation of the germ line up-regulates DA/DAF-12 signaling. (A) Time course of daf-36 mRNA level in WT and germline-less animals (glp-1). Error bars denote SEM. (B and C) 7-dehydrocholestrol (B) and {Delta}7-DA (C) are elevated in germline-less animals. t test; **P < 0.01, ***P < 0.001. (D) Time course of mir-84 and mir-241 levels in WT and glp-1 animals. (E) In glp-1 animals, mir-84p::gfp and mir-241p::gfp expression are up-regulated in seam cells (arrowheads) and intestine (arrows), respectively. (F and G) Germline absence results in up-regulation of mir-84 and mir-241 in a DAF-12/DA–dependent manner. Strains were grown on plates supplemented with ethanol (EtOH) or {Delta}4-dafachronic acid (DA). Analysis of variance (ANOVA) versus glp-1 EtOH; ns, nonsignificant. *P < 0.05, **P < 0.01, ***P < 0.001.


Figure 2
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Fig. 2. DAF-12 target miRNAs are required for gonadal longevity through DAF-16/FOXO. (A) mir-84 and mir-241 are required for gonadal longevity. Laser microsurgery was performed to ablate the germ line. (B) mir-84 and mir-241 do not affect the longevity by reduced IR signaling (daf-2RNAi) or mitochondrial function (cco-1RNAi). (C) Life-span analysis of indicated strains on daf-16RNAi. (D) Quantitative real time PCR of DAF-16/FOXO target genes (T08B1.1 and btb-14) in worms of indicated genotypes. ANOVA; *P < 0.05, **P < 0.01, ***P < 0.001.


Figure 3
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Fig. 3. akt-1 kinase is a miRNA target influencing gonadal longevity. (A and B) mir-84 and mir-241 target the 3'UTR of akt-1 but not unc-1 in vivo. Although GFP driven by the akt-1 promoter in the DR construct remains similar, red fluorescent protein controlled by the akt-1 3'UTR is significantly elevated in mir-84;mir-241. (C and D) akt-1-3'UTR-DR is down-regulated in germline-less animals. 17 WT and 29 glp-1 worms at D1 were examined from microscopic photos. t test; ***P < 0.001. (E) akt-1RNAi increases the life span of mir-84;mir-241;glp-1 and glp-1 to the same absolute extent. A.U., arbitrary units; n, number of animals.


Figure 4
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Fig. 4. The lin-14 heterochronic locus is a miRNA target regulating gonadal longevity. (A) lin-14RNAi restores longevity to mir-84;mir-241;glp-1. (B and C) DR construct with the 3'UTR of lin-14 but not of unc-1 is up-regulated in mir-84;mir-241 animals compared with WT animals. Arrowheads denote intestinal nuclei. (D and E) lin-14-3'UTR-DR is down-regulated in glp-1. Arrowheads denote intestinal nuclei. For each genotype, 60 intestinal cells from 20 worms were analyzed. t test; ***P < 0.001. (F) lin-14RNAi or akt-1RNAi increases lipl-4 expression in mir-84;mir-241;glp-1. ANOVA; *P < 0.05, **P < 0.01.


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