dbl-1/TGF-β and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest.

Kaplan, RE

Chen, Y

Moore, BT

Jordan, JM

Maxwell, CS

Schindler, AJ

Baugh, LR

United States

2016-12-14T18:51:15Z

2015-12

Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

http://www.ncbi.nlm.nih.gov/pubmed/26656736

PGENETICS-D-15-01311

1553-7404

https://hdl.handle.net/10161/13272

eng

Public Library of Science

PLoS Genet

10.1371/journal.pgen.1005731

Animals

Caenorhabditis elegans

Caenorhabditis elegans Proteins

Embryo, Nonmammalian

Embryonic Development

Forkhead Transcription Factors

Gene Expression Regulation, Developmental

Humans

Insulin

Larva

Neuropeptides

RNA, Messenger

Receptors, Cytoplasmic and Nuclear

Signal Transduction

Somatomedins

Starvation

Transforming Growth Factor beta

dbl-1/TGF-β and daf-12/NHR Signaling Mediate Cell-Nonautonomous Effects of daf-16/FOXO on Starvation-Induced Developmental Arrest.

Journal article

Baugh, LR|0000-0003-2148-5492

http://www.ncbi.nlm.nih.gov/pubmed/26656736

e1005731

12

Biology

Duke

Trinity College of Arts & Sciences

Published online

11