Inhibition of ribosome biogenesis in the epidermis is sufficient to trigger organism-wide growth quiescence independently of nutritional status in C. elegans

Abstract

Interorgan communication is crucial for multicellular organismal growth, development, and homeostasis. Cell nonautonomous inhibitory cues, which limit tissue-specific growth alterations, are not well characterized due to cell ablation approach limitations. In this study, we employed the auxin-inducible degradation system in C. elegans to temporally and spatially modulate ribosome biogenesis, through depletion of essential factors (RPOA-2, GRWD-1, or TSR-2). Our findings reveal that embryo-wide inhibition of ribosome biogenesis induces a reversible early larval growth quiescence, distinguished by a unique gene expression signature that is different from starvation or dauer stages. When ribosome biogenesis is inhibited in volumetrically similar tissues, including body wall muscle, epidermis, pharynx, intestine, or germ line, it results in proportionally stunted growth across the organism to different degrees. We show that specifically inhibiting ribosome biogenesis in the epidermis is sufficient to trigger an organism-wide growth quiescence. Epidermis-specific ribosome depletion leads to larval growth quiescence at the L3 stage, reduces organism-wide protein synthesis, and induced cell nonautonomous gene expression alterations. Further molecular analysis reveals overexpression of secreted proteins, suggesting an organism-wide regulatory mechanism. We find that UNC-31, a dense-core vesicle (DCV) pathway component, plays a significant role in epidermal ribosome biogenesis-mediated growth quiescence. Our tissue-specific knockdown experiments reveal that the organism-wide growth quiescence induced by epidermal-specific ribosome biogenesis inhibition is suppressed by reducing unc-31 expression in the epidermis, but not in neurons or body wall muscles. Similarly, IDA-1, a membrane-associated protein of the DCV, is overexpressed, and its knockdown in epidermis suppresses the organism-wide growth quiescence in response to epidermal ribosome biogenesis inhibition. Finally, we observe an overall increase in DCV puncta labeled by IDA-1 when epidermal ribosome biogenesis is inhibited, and these puncta are present in or near epidermal cells. In conclusion, these findings suggest a novel mechanism of nutrition-independent multicellular growth coordination initiated from the epidermis tissue upon ribosome biogenesis inhibition.