Our lab is working on the C. elegans Axin-like scaffolding protein PRY-1 for its involvement in reproductive system development and aging [1, 2]. PRY-1 has been studied mainly in the context of canonical WNT signaling to regulate developmental processes. Since Axin family members also interact with WNT-independent pathways, pry-1 serves as a useful genetic tool to investigate the conserved mechanism of function of Axin proteins. During the process of investigating pry-1 role in worms, we found that pry-1 mutants have reduced lipid levels as well as a drastic reduction in lifespan. In agreement with the lowered lipid content, mutant worms also have smaller brood size and poor L1 survival. To understand how pry-1 regulates these processes, we set out to identify interacting genes using a genome-wide RNA-seq experiment in pry-1(mu38) strain. As expected from the phenotypes, the transcriptome profiling of pry-1 mutant revealed differentially expressed genes associated with aging and lipid metabolism, such as vitellogenins (yolk lipoproteins, vit), fatty acid desaturases, lipases, and fatty acid transporters. The expression of vits was found to be significantly upregulated in animals lacking pry-1 function. Additionally, knockdown of vit genes in a pry-1 mutant background restored lipid levels, suggesting that vitellogenins contribute to PRY-1 role in lipid metabolic processes. The reduced levels of lipids in pry-1 mutants led us to investigate changes in lipid metabolic pathways. Our Gas Chromatography-Mass Spectrometry analysis, combined by transcriptomic and other gene expression data, provided evidence that fatty acid synthesis is significantly reduced in pry-1 mutants. Consistent with this, an exogenous supply of oleic acid (mono-unsaturated fatty acid) restored lipids in somatic tissues of the mutant worms. We also found that sbp-1, one of the transcription factors involved in the regulation of desaturases is significantly downregulated in animals lacking pry-1 function. Since nhr-49 and nhr-80, two nuclear hormone receptor family members, are known regulators of fatty acid synthesis, we examined their role in pry-1 signaling. Our genetic interaction studies suggest that both these transcription factors act in parallel to sbp-1-mediated pry-1 pathway. Current research in the lab focuses on the mechanism of pry-1 function in lipid synthesis and its potential role in lifespan maintenance. References: [1] Ranawade A, Mallick A and Gupta BP (2018). PRY-1/Axin signaling regulates lipid metabolism in Caenorhabditis elegans. PLoS ONE 13(11):e0206540. [2] Seetharaman A, Cumbo P, Bojanala N and Gupta BP (2010). Conserved mechanism of Wnt signaling function in the specification of vulval precursor fates in C. elegans and C. briggsae. Dev Bio. 346(1):128-139.

Affiliations:
- Department of Biology, McMaster University
- Department of Physics, Harvard University