CDK-4 regulates nucleolar size and metabolism at the cost of late-life fitness in C. elegans
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Abstract
An outstanding question in biology concerns mechanisms of size control in organs, cells, and organelles. Size impacts metabolic efficiency, surface area-to-volume ratio, and environmental adaptation, which are all required for optimal function. Cyclin-dependent kinase 4 (CDK4), traditionally recognized for its role in cell cycle progression, has gained increasing support for cell cycle-independent roles. Previously, we described a mechanism of cell size control involving a CDK4 and p38 MAPK circuitry that dictates target cell size. In this study, we target the CDK4/6 ortholog CDK-4 in the nematode worm Caenorhabditis elegans to describe functional consequences of changing biological size in vivo . Our data suggest that CDK-4 regulates nucleolar size and anabolic metabolism independent from cell cycle progression. When size and metabolism are increased, we report enhanced thermotolerance early in life but accelerated aging and reduced longevity late in life, suggesting a novel function of CDK-4 in somatic maintenance and organism health.
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Mutations were generated in the HS3545 background, which ubiquitously expresses the TIR1(F79G) receptor,
love the power of auxin/aid system in this paper! If you ever want/need cell-type specific control also, we made a bunch of tools in https://doi.org/10.1093/genetics/iyad013 that might be super useful so you could visualize cell cycle state and get robust auxin-mediated depletion in whatever lineage you want (would just need to pair this with seam-cell promoter FLP).
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In control populations under these conditions, up to 10% of the population will survive this heat shock. However, after CDK-4 ablation 56% of the population survived the same heat shock treatment (Figure 5B). Although LIN-35 ablation had no significant effect on heat stress survival, co-ablation with CDK-4 suppressed survival to wildtype levels (Figure 5B). These results suggest that when nucleoli are large and protein synthesis is high, the animal is better equipped to survive phases of acute heat stress.
This is such an amazing result! It makes me wonder if tuning CDK-4 activity (or maybe just nucleolar size in general???) could be an evolutionary selection criteria for thermotolerance in higher temperature environments? Are there wild isolates of C. elegans from warm climates that have bigger nucleoli than cold-isolated isolates …
In control populations under these conditions, up to 10% of the population will survive this heat shock. However, after CDK-4 ablation 56% of the population survived the same heat shock treatment (Figure 5B). Although LIN-35 ablation had no significant effect on heat stress survival, co-ablation with CDK-4 suppressed survival to wildtype levels (Figure 5B). These results suggest that when nucleoli are large and protein synthesis is high, the animal is better equipped to survive phases of acute heat stress.
This is such an amazing result! It makes me wonder if tuning CDK-4 activity (or maybe just nucleolar size in general???) could be an evolutionary selection criteria for thermotolerance in higher temperature environments? Are there wild isolates of C. elegans from warm climates that have bigger nucleoli than cold-isolated isolates (or just N2?). Or do you think the negative selection on aging might counter-balance this?
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