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• W4386049718 abstract "Abstract Nuclear hormone receptors (NHRs) are a deeply-conserved superfamily of metazoan transcription factors, which fine-tune the expression of their regulatory target genes in response to a plethora of sensory inputs. In nematodes, NHRs underwent an explosive expansion and many species have hundreds of nhr genes, most of which remain functionally uncharacterized. However, recent studies elucidated that two sister receptors, Ppa- NHR-1 and Ppa- NHR-40, are crucial down-stream regulators of feeding plasticity in the diplogastrid model organism Pristionchus pacificus . In this study, we functionally characterize Ppa- NHR-10, the closest paralog to Ppa- NHR-1 and Ppa- NHR-40, aiming to demonstrate that it too regulates aspects of feeding plasticity. We used CRISPR/CAS9-mediated mutagenesis to create knock-out mutations of this receptor and applied a combination of geometric morphometrics and unsupervised clustering to characterize potential mutant phenotypes. Surprisingly, we found that Ppa- NHR-10 is not involved in the regulation of plasticity in feeding structures. Instead, multiple RNA-seq experiments revealed that many of the target genes of this receptor are crucial for lipid catabolism. We hypothesized that their mis-regulation could affect the survival of mutant worms during starvation, where lipid catabolism is often essential. Using survival assays, we found that mutant worms indeed show drastically decreased starvation resistance, both as young adults and as dauer larvae. We also characterized genome-wide changes to the transcriptional landscape in P. pacificus when exposed to 24hrs of acute starvation, and found that Ppa- NHR-10 partially regulates some of these responses. Taken together, we were able to demonstrate that Ppa- NHR-10 is broadly required for starvation resistance and regulates different biological processes than its closest paralogs Ppa- NHR-1 and Ppa- NHR-40 and its one-to-one ortholog in Caenorhabditis elegans. This shows that, amongst distantly-related model nematodes, even deeply-conserved NHRs can regulate vastly distinct biological processes and that neither paralogs, nor one-to-one orthologs, may be adequate predictors of their biological functions. Author summary When predicting the biological function of a gene (or the protein it encodes) we usually use its homologs for reference since it is likely that our gene or protein of interest has homologs in a different organism (orthologs) or in the same organism (paralogs), whose biological roles have already been characterized via molecular genetic interventions. However, predicting biological functions from homologs can have its limitations. In this study, we functionally characterized a conserved nuclear receptor, Ppa- NHR-10, in the nematode Pristionchus pacificus and found that both dauer larvae (a specialized dispersal stage) and adult worms are less resistant to starvation if this receptor is experimentally rendered non-functional. Not only did these findings reveal that Ppa- NHR-10 is crucial for the worms to survive harsh conditions they would frequently encounter in the wild, they also demonstrated that Ppa- NHR-10’s homologs would not have been adequate predictors of its biological role: its homolog in Caenorhabditis elegans regulates a metabolic shunt pathway; its paralogs in P. pacificus regulate feeding plasticity. Thus, our data suggests that conserved nuclear receptors can functionally diversify across distantly-related nematodes, and that we cannot categorically infer their biological roles from well-studied homologs." @default.
• W4386049718 created "2023-08-23" @default.
• W4386049718 creator A5023296857 @default.
• W4386049718 creator A5025481491 @default.
• W4386049718 creator A5085907118 @default.
• W4386049718 date "2023-08-21" @default.
• W4386049718 modified "2023-10-10" @default.
• W4386049718 title "Starvation resistance in the nematode<i>Pristionchus pacificus</i>requires a conserved supplementary nuclear receptor" @default.
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