Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing

Abstract

Motivation: A large number of experimental studies on ageing focus on the effects of genetic perturbations of the insulin/insulin-like growth factor signalling pathway (IIS) on lifespan. Short-lived invertebrate laboratory model organisms are extensively used to quickly identify ageing-related genes and pathways. It is important to extrapolate this knowledge to longer lived mammalian organisms, such as mouse and eventually human, where such analyses are difficult or impossible to perform. Computational tools are needed to integrate and manipulate pathway knowledge in different species. Results: We performed a literature review and curation of the IIS and target of rapamycin signalling pathways in Mus Musculus. We compare this pathway model to the equivalent models in Drosophila melanogaster and Caenorhabtitis elegans. Although generally well-conserved, they exhibit important differences. In general, the worm and mouse pathways include a larger number of feedback loops and interactions than the fly. We identify 'functional orthologues' that share similar molecular interactions, but have moderate sequence similarity. Finally, we incorporate the mouse model into the web-service NetEffects and perform in silico gene perturbations of IIS components and analyses of experimental results. We identify sub-paths that, given a mutation in an IIS component, could potentially antagonize the primary effects on ageing via FOXO in mouse and via SKN-1 in worm. Finally, we explore the effects of FOXO knockouts in three different mouse tissues.