Stochastic loss and gain of symmetric divisions in the C. elegans epidermis perturbs robustness of stem cell number

• Published in: PLoS biology Vol. 15; no. 11; p. e2002429
• Main Authors: Katsanos, Dimitris, Koneru, Sneha L., Mestek Boukhibar, Lamia, Gritti, Nicola, Ghose, Ritobrata, Appleford, Peter J., Doitsidou, Maria, Woollard, Alison, van Zon, Jeroen S., Poole, Richard J., Barkoulas, Michalis
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.11.2017; Public Library of Science (PLoS)
• Subjects: Animals; Biochemistry; Biology and Life Sciences; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Count; Cell Differentiation; Cell Division; Cell Lineage; Cell number; Cells, Cultured; CRISPR; Data collection; Developmental biology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epidermal Cells; Epidermis; Epidermis - metabolism; Feasibility studies; Gene expression; Gene Expression Regulation; Genetic variability; Genetics; Genomes; Helix-loop-helix proteins; Helix-loop-helix proteins (basic); Life sciences; Molecular physics; Mutagenesis; Mutants; Mutation; Nematodes; Physiological aspects; Research and Analysis Methods; Screens; Signal transduction; Signaling; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Stochastic Processes; Stochasticity; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; University colleges; Variability; Wnt protein; Wnt Signaling Pathway
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.2002429

Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout. We employ genetics, cell lineage tracing, and single molecule imaging to show that mutations in lin-22, a Hes-related basic helix-loop-helix (bHLH) transcription factor, increase seam cell number variability. We show that the increase in phenotypic variability is due to stochastic conversion of normally symmetric cell divisions to asymmetric and vice versa during development, which affect the terminal seam cell number in opposing directions. We demonstrate that LIN-22 acts within the epidermal gene network to antagonise the Wnt signalling pathway. However, lin-22 mutants exhibit cell-to-cell variability in Wnt pathway activation, which correlates with and may drive phenotypic variability. Our study demonstrates the feasibility to study phenotypic trait variance in tractable model organisms using unbiased mutagenesis screens.