Opposing action of the FLR-2 glycoprotein hormone and DRL-1/FLR-4 MAP kinases balance p38-mediated growth and lipid homeostasis in C. elegans.

Animals integrate developmental and nutritional signals before committing crucial resources to growth and reproduction; however, the pathways that perceive and respond to these inputs remain poorly understood. Here, we demonstrate that DRL-1 and FLR-4, which share similarity with mammalian mitogen-activated protein kinases, maintain lipid homeostasis in the C. elegans intestine. DRL-1 and FLR-4 function in a protein complex at the plasma membrane to promote development, as mutations in drl-1 or flr-4 confer slow growth, small body size, and impaired lipid homeostasis. To identify factors that oppose DRL-1/FLR-4, we performed a forward genetic screen for suppressors of the drl-1 mutant phenotypes and identified mutations in flr-2 and fshr-1, which encode the orthologues of follicle stimulating hormone and its putative G protein-coupled receptor, respectively. In the absence of DRL-1/FLR-4, neuronal FLR-2 acts through intestinal FSHR-1 and protein kinase A signaling to restrict growth. Furthermore, we show that opposing signaling through DRL-1 and FLR-2 coordinates TIR-1 oligomerization, which modulates downstream p38/PMK-1 activity, lipid homeostasis, and development. Finally, we identify a surprising noncanonical role for the developmental transcription factor PHA-4/FOXA in the intestine where it restricts growth in response to impaired DRL-1 signaling. Our work uncovers a complex multi-tissue signaling network that converges on p38 signaling to maintain homeostasis during development.

The TWK-26 potassium channel governs nutrient absorption in the C. elegans intestine.

Ion channels are necessary for proper water and nutrient absorption in the intestine, which supports cellular metabolism and organismal growth. While a role for Na + co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K + uniporters function to maintain ion homeostasis is poorly understood. Using Caenorhabditis elegans , we show that a gain-of-function mutation in twk-26 , which encodes a two-pore domain K + ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects displayed by impaired intestinal MAP Kinase (MAPK) signaling. Mutations in drl-1 and flr-4, which encode two components of this MAPK pathway, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes, which mirror dietary restriction phenotypes. Additionally, these MAPK mutants display structural defects of the intestine and an impaired defecation motor program. We find that activation of TWK-26 reverses the dietary restriction-like state of the MAPK mutants by restoring intestinal nutrient absorption without correcting the intestinal bloating or defecation defects. This study provides unique insight into the mechanisms by which intestinal K + ion channels support intestinal metabolic homeostasis.

The C. elegansflr-3(ut9) mutation is a loss-of-function insertion within the drl-1 locus.

The genes encoding the mitogen-activated protein kinases DRL-1 and FLR-4 are required for growth and lipid homeostasis in C. elegans . Interestingly, the flr-3 ( ut9 ) mutant, which was previously isolated in a forward genetic screen for mutations that confer fluoride resistance, phenocopies the drl-1 and flr-4 loss-of-function mutants; however, the genetic identity of flr-3 is unknown. Through whole genome sequencing, we found that the flr-3 ( ut9 ) mutation is an insertion in the drl-1 locus and disrupts drl-1 gene function, resulting in dramatic growth defects and impaired vitellogenin production.