InsR/IGF1R signalling and microRNAs in C. elegans development and longevity
The Ruvkun lab works on two major themes: regulation by microRNA genes and other small RNAs, and control of longevity and metabolism by insulin and other endocrine pathways. With Victor Ambros, Ruvkun discovered that the developmental switch gene lin-14 is regulated by the 21 nucleotide lin-4 microRNA, which basepairs to complementary regulatory elements in the lin-14 3’ untranslated region to repress translation. Ruvkun identified a second microRNA, let-7, which also regulates translation of its target gene via imperfect base pairing to the 3’ untranslated region of that mRNA, and showed that the sequence and regulation of the let-7 microRNA is conserved across animal phylogeny. This was the first indication that miRNA regulation via 3’ UTR complementarity was a general phenomenon. Thousands of miRNAs have subsequently been discovered and are now implicated in control of gene expression of across eukaryotic phylogeny. Saturation genetic analysis of the miRNA and RNAi pathways by the Ruvkun lab has revealed many of the protein cofactors that may mediate other steps in how miRNAs and siRNAs engage their targets. The Ruvkun lab discovered that there is complex negative regulation of RNAi and competing small RNA pathways. These components may be developed as drug targets to enhance RNAi in mammals, to elevate a laboratory tool to a therapeutic modality.
Dr. Ruvkun’s laboratory has also discovered that an insulin-like signaling pathway controls C. elegans metabolism and longevity. Saturation genetic analysis of the pathway in the Ruvkun laboratory identified most of the signaling components, including daf-16, a Forkhead transcription factor that illuminated the function of the mammalian FoxO transcription factors, now intensively studied as insulin signaling transcriptional outputs. These findings are also important for the eventual treatment of diabetes, a disease of insulin signaling.
Dr. Ruvkun’s lab has also used full genome RNAi libraries to explore the complete set of genes that regulate aging and metabolism. Many of these genes are broadly conserved in animal phylogeny. Many of the gene inactivations that cause increased longevity encode the core conserved proteins. Inactivation of these core genes may induce an endocrine state of drug detoxification and longevity induction. The endocrine states that are normally induced by poisons and variation in the conserved detoxification response pathway may underlie diseases not normally thought of as xenobiotic response dysregulations.
1. Melo, JA and G. Ruvkun. 2012. Inactivation of essential cellular pathways stimulates microbial avoidance behavior, drug detoxification, and pathogen defense-related responses in C. elegans. Cell 149:452-66. PMCID: PMC3613046
2. Zhang, C., TA Montgomery, SE Fischer, SM Garcia, CG Riedel, N Fahlgren, CM Sullivan, JC Carrington and G Ruvkun. 2012. The Caenorhabditis elegans RDE-10/RDE-11 complex regulates RNAi by promoting secondary siRNA amplification. Current Biology 22:881-90. Epub Apr 26. PMCID: PMC3371361
3. Phillips, CM, PC Breen, TA Montgomery and G Ruvkun. 2012. MUT-16 defines a perinuclear granule required for siRNA production in the germline. Genes and Development 26:1433-44. Epub Jun 19. PMCID: PMC3403012
4. Shore DE, CE Carr and G Ruvkun. 2012. Induction of cytoprotective pathways is central to the extension of lifespan conferred by multiple longevity pathways. PloS Genetics 8(7):e1002792. PMCID: PMC3400582
5. Tabach, Y, A Billi, G Hayes, O Zuk, H Gabel, R Kamath, M. Newman, K Yacoby, B Chapman, M Borowsky, J Kim, G Ruvkun. 2013. Identification of new small RNA pathway genes from correlated patterns of phylogenetic retention and loss. Nature Jan 31;493(7434):694-8. doi: 10.1038/nature11779. Epub 2012 Dec 23. PMCID: PMC3762460
6. Shi, Z, T Montgomery, Y Qi and G Ruvkun. 2013. High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA and siRNA pathways in nematodes. Genome Research Mar;23(3):497-508. doi: 10.1101/gr.149112.112. Epub 2013 Jan 30. PMCID: PMC3589538
7. O’Rourke, EA, P Kuballa, R Xavier, and G Ruvkun. 2013. w-6 Polyunsaturated Fatty Acids Promote Survival through Activation of Autophagy. Genes and Development Feb 15;27(4):429-40. doi: 10.1101/gad.205294.112. Epub 2013 Feb 7. PMCID: PMC3589559
8. Riedel, CG, G Lima, NV. Kirienko, T Heimbucher, JA West, A Dillin, J Asara, and G Ruvkun. 2013. DAF-16/FOXO employs the chromatin remodeller SWI/SNF to promote longevity. Nature Cell Biology, 2013 May;15(5):491-501. doi: 10.1038/ncb2720. Epub 2013 Apr 21. PMCID: PMC3748955
9. O’Rourke, EA and G Ruvkun. 2013. The Hlh-30/Mxl-3 transcriptional circuit coordinates lipolysis and autophagy. Nature Cell Biology, 2013 Jun;15(6):668-76. doi: 10.1038/ncb2741. Epub 2013 Apr 21. PMCID: PMC3723461