A folder mechanism ensures size uniformity amongC. elegansindividuals by coupling growth and development

Abstract

Animals increase by orders of magnitude in their volume during development. Hence, even small differences in the growth rates between individuals could generate large differences in their adult body size. Yet, such volume divergence among individuals is usually not observed in nature.We combined theory and experiment to understand the mechanisms of body size uniformity. Using live imaging, we measured the volume growth of hundreds of individuals of C. elegans over the entire span of their postembryonic development. We find that C. elegans grows exponentially in volume with a coefficient of variation of the growth rate of ∼7%, but that individuals diverge much less in volume than expected from this heterogeneity. The mechanism counteracting size divergence does not involve size thresholds for developmental milestones. Instead, an inverse coupling of the growth rate and the duration of development produces a constant volume fold change per larval stage.The duration of larval stages of C. elegans is determined by the period of a developmental oscillator. Using mathematical modelling, we show that an anti-correlation between the growth rate and the oscillatory period emerges as an intrinsic property of a genetic oscillator. We propose that the robustness of body volume fold change is a hard-wired characteristic of the oscillatory circuit and does not require elaborate mechanisms of size control by cellular signalling. Indeed, the coupling of growth and development was unaltered by mutation of canonical pathways of growth control. This novel concept of size homeostasis may broadly apply to other multicellular systems controlled by genetic oscillators.

Changes in body shape implicate cuticle stretch inC. elegansgrowth control

“…In this way, smaller animals would reach a stretch limit at a smaller size as the cuticle would only stretch a percentage of its original size before reaching a threshold. A folder mechanism for C. elegans growth has been previously suggested (Towbin and Grosshans, 2021) . For cuticle stretch to trigger larval-stage transitions, animals must either have the ability to measure the amount the cuticle has stretched or the stiffness of the cuticle.…”

“…Because individuals in a population maintain similar sizes despite differences in growth rate, a control mechanism to regulate developmental progression must exist. Early work proposed a size-based growth control model in C. elegans (Uppaluri and Brangwynne, 2015) , while recent work suggests that size homeostasis is achieved through a folder mechanism where growth rate and development are coupled (Towbin and Grosshans, 2021) . To assess changes in body size and shape during a larval transition, we examined the dynamics of animal length, width, and volume in the hours before, during, and after each molt.…”

“…Previous studies theorized that the internal mechanism for sensing body size and triggering molts in C. elegans is driven, in part, by the properties of the collagen-rich cuticle (Towbin and Grosshans, 2021;Uppaluri and Brangwynne, 2015) . Many cuticle collagen mutations cause morphological defects in nematode shape some of which cause animals to be shorter but do not impact animal width, implying that the cuticle affects length and width independently (Brenner, 1974) .…”

“…This difference in growth requires a size-based control mechanism to ensure that growth is halted once a maximum size is reached. Although 'Timer' and 'Sizer' are the most often proposed size-control models, other models have been suggested, including 'Adder' in which a fixed volume is added to a cell or organism during growth (Campos et al, 2014;Taheri-Araghi et al, 2015) , and 'Folder' in which the organism increases in volume by a fixed proportion (Towbin and Grosshans, 2021) . It is not trivial to determine which model most accurately describes growth of individual cells or whole organisms because quantitative measurements of growth must be collected at high precision and throughput under tightly controlled experimental conditions.…”

Differential regulation of developmental stages supports a linear model forC. eleganspostembryonic development

“…This are only some of the stage-specific events during larval development but, with this in mind, it seems remarkable that the duration of the stages is so similar. A recent work has revealed coupling between growth rate and developmental timing (Towbin and Großhans, 2021). The authors suggest two possible non-exclusive mechanisms to achieve this coupling.…”