Abstract
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.
Highlights
It is remarkable how biological systems manage to operate consistently despite facing several types of variation, including the intrinsic stochasticity in every molecular process
To study the genetic mechanisms underpinning the consistency of seam cell number among individuals, we set out to isolate mutants showing an increase in seam cell number variance
Variability is defined in this screen at the level of the population, so we hypothesised that the selected animals would either show in the generation a variable seam cell number phenotype (Vsc) or alternatively an increase or decrease in terminal seam cell number (Fig 1B)
Summary
It is remarkable how biological systems manage to operate consistently despite facing several types of variation, including the intrinsic stochasticity in every molecular process This ability of a given system to produce an invariable output in the presence of internal and external perturbations is called robustness [1, 2]. Genome-wide mutagenesis screens to identify factors shaping phenotypic variability have not been performed in multicellular animals It remains largely unclear: (1) what are the genes that modulate developmental trait variance as a response to a specific perturbation, (2) how these genes fit in developmental gene networks, and (3) what their specificity is to the phenotypic trait of interest within the context of a whole organism
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