Merrow, M. | Search bioRxiv

bioRxiv2018

Prolonged quiescence delays somatic stem cell-like division in Caenorhabditis elegans and is controlled by insulin signalling

Cells can enter quiescence in adverse conditions and resume proliferation when the environment becomes favourable. Prolonged quiescence comes with a cost, reducing proliferation potential and survival. Interestingly, cellular quiescence also occurs in normal development, with many cells spending most of their lifetime at this state. Elucidating the mechanisms involved in surviving long-term quiescence and in maintenance of cellular proliferation potential will contribute to a better understanding of the process of tissue regeneration. Developmental arrest of C. elegans at the L1 stage is an emerging model for the study of cellular quiescence and reactivation. During arrest, L1 larvae undergo a process that shares phenotypic hallmarks with the ageing of the adult. Interestingly, insulin signalling, a prominent pathway in the regulation of ageing, also balances cell proliferation and activation of stress resistance pathways during quiescence, becoming a candidate regulator of proliferation potential. Here we report that prolonged L1 quiescence delays reactivation of blast cell divisions in C. elegans, leading to a delay in the initiation of postembryonic development. This delay is accompanied by increased inter-individual variability. We propose that the delay in cell division results from the decline that animals suffer during L1 arrest. To that end, we show that insulin signalling modulates the rate of L1 ageing, affecting proliferative potential after quiescence. These findings support that the insulin signalling pathway has a comparable role in L1 arrest to that in ageing adults. Furthermore, we show that variable yolk provisioning to the embryos as a consequence of maternal age is one of the sources of inter-individual variability in recovery after quiescence of genetically identical animals. Taken together, these results support the relevance of L1 arrest as a model to study in vivo proliferation after quiescence and to understand the mechanisms for maintenance of proliferation potential.

developmental biology↗

bioRxiv2018

PREMONition: An algorithm for predicting the circadian clock-regulated molecular network

A transcriptional feedback loop is central to clock function in animals, plants and fungi. The clock genes involved in its regulation are specific to - and highly conserved within - the kingdoms of life. However, other shared clock mechanisms, such as phosphorylation, are mediated by proteins found broadly among living organisms, performing functions in many cellular sub-systems. Use of homology to directly infer involvement/association with the clock mechanism in new, developing model systems, is therefore of limited use. Here we describe the approach PREMONition, PREdicting Molecular Networks, that uses functional relationships to predict molecular circadian clock associations. PREMONition is based on the incorporation of proteins encoded by known clock genes (when available), rhythmically expressed clock-controlled genes and non-rhythmically expressed but interacting genes into a cohesive network. After tuning PREMONition on the networks derived for human, fly and fungal circadian clocks, we deployed the approach to predict a molecular clock network for Saccharomyces cerevisiae, for which there are no readily-identifiable clock gene homologs. The predicted network was validated using gene expression data and a growth assay for sensitivity to light, a zeitgeber of circadian clocks of most organisms. PREMONition may be used to identify candidate clock-regulated processes and thus candidate clock genes in other organisms.

bioinformatics↗