Abstract
Argonaute (AGO) proteins partner with microRNAs (miRNAs) to target specific genes for post-transcriptional regulation. During larval development in Caenorhabditis elegans, Argonaute-Like Gene 1 (ALG-1) is the primary mediator of the miRNA pathway, while the related ALG-2 protein is largely dispensable. Here we show that in adult C. elegans these AGOs are differentially expressed and, surprisingly, work in opposition to each other; alg-1 promotes longevity, whereas alg-2 restricts lifespan. Transcriptional profiling of adult animals revealed that distinct miRNAs and largely non-overlapping sets of protein-coding genes are misregulated in alg-1 and alg-2 mutants. Interestingly, many of the differentially expressed genes are downstream targets of the Insulin/ IGF-1 Signaling (IIS) pathway, which controls lifespan by regulating the activity of the DAF-16/ FOXO transcription factor. Consistent with this observation, we show that daf-16 is required for the extended lifespan of alg-2 mutants. Furthermore, the long lifespan of daf-2 insulin receptor mutants, which depends on daf-16, is strongly reduced in animals lacking alg-1 activity. This work establishes an important role for AGO-mediated gene regulation in aging C. elegans and illustrates that the activity of homologous genes can switch from complementary to antagonistic, depending on the life stage.
Highlights
As components of the microRNA induced silencing complex, miRNAs use partial base pairing to tether Argonaute (AGO) and associated proteins to specific target RNAs, typically resulting in RNA destabilization [1]
Previous studies have shown that the predominant miRNA Argonautes, Argonaute-Like Gene 1 (ALG-1) and ALG-2, are expressed constitutively in developing C. elegans, with the highest levels detected in embryos [5, 8]
Since loss of alg-1 reduces C. elegans lifespan and expression of this AGO was observed to be down-regulated with age, we considered the possibility that alg-2 mutants might express higher levels of ALG-1 and depend on this factor for their extended lifespan phenotype
Summary
As components of the microRNA (miRNA) induced silencing complex (miRISC), miRNAs use partial base pairing to tether Argonaute (AGO) and associated proteins to specific target RNAs, typically resulting in RNA destabilization [1]. Target regulation by miRNAs is dependent on the availability and function of AGO proteins. The alg-1 and alg-2 genes encode proteins that are over 75% identical at the amino acid level and appear to share similar spatiotemporal expression patterns during embryogenesis and larval development [8, 9]. Alg-1 loss-of-function mutants exhibit mild to severe developmental defects, alg-2 null mutants appear to develop normally [6, 8,9,10]. ALG-1 appears to serve as the primary AGO for the miRNA pathway during development with ALG2 contributing mostly redundant functions
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