SummarySleep is ancient and fulfills higher brain functions as well as basic vital processes. Little is known about how sleep emerged in evolution and what essential functions it was selected for. Here, we investigated sleep in Caenorhabditis elegans across developmental stages and physiological conditions to find out when and how sleep in a simple animal becomes essential for survival. We found that sleep in worms occurs during most stages and physiological conditions and is typically induced by the sleep-active RIS neuron. Food quality and availability determine sleep amount. Extended starvation, which induces developmental arrest in larvae, presents a major sleep trigger. Conserved nutrient-sensing regulators of longevity and developmental arrest, AMP-activated kinase and FoxO, act in parallel to induce sleep during extended food deprivation. These metabolic factors can act in multiple tissues to signal starvation to RIS. Although sleep does not appear to be essential for a normal adult lifespan, it is crucial for survival of starvation-induced developmental arrest in larvae. Rather than merely saving energy for later use, sleep counteracts the progression of aging phenotypes, perhaps by allocating resources. Thus, sleep presents a protective anti-aging program that is induced by nutrient-sensing longevity pathways to survive starvation-induced developmental arrest. All organisms are threatened with the possibility of experienced famine in their life, which suggests that the molecular coupling of starvation, development, aging, and sleep was selected for early in the evolution of nervous systems and may be conserved in other species, including humans.
Despite major advances on miRNA profiling and target predictions, functional readouts for endogenous miRNAs are limited and frequently lead to contradicting conclusions. Numerous approaches including functional high-throughput and miRISC complex evaluations suggest that the functional miRNAome differs from the predictions based on quantitative sRNA profiling. To resolve the apparent contradiction of expression versus function, we generated and applied a fluorescence reporter gene assay enabling single cell analysis. This approach integrates and adapts a mathematical model for miRNA-driven gene repression. This model predicts three distinct miRNA-groups with unique repression activities (low, mid and high) governed not just by expression levels but also by miRNA/target-binding capability. Here, we demonstrate the feasibility of the system by applying controlled concentrations of synthetic siRNAs and in parallel, altering target-binding capability on corresponding reporter-constructs. Furthermore, we compared miRNA-profiles with the modeled predictions of 29 individual candidates. We demonstrate that expression levels only partially reflect the miRNA function, fitting to the model-projected groups of different activities. Furthermore, we demonstrate that subcellular localization of miRNAs impacts functionality. Our results imply that miRNA profiling alone cannot define their repression activity. The gene regulatory function is a dynamic and complex process beyond a minimalistic conception of “highly expressed equals high repression”.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.