Regulation of signaling genes by TGFbeta during entry into dauer diapause in C. elegans

BMC Dev Biol. 2004 Sep 20;4:11. doi: 10.1186/1471-213X-4-11.

Abstract

Background: When resources are scant, C. elegans larvae arrest as long-lived dauers under the control of insulin/IGF- and TGFbeta-related signaling pathways. However, critical questions remain regarding the regulation of this developmental event. How do three dozen insulin-like proteins regulate one tyrosine kinase receptor to control complex events in dauer, metabolism and aging? How are signals from the TGFbeta and insulin/IGF pathways integrated? What gene expression programs do these pathways regulate, and how do they control complex downstream events?

Results: We have identified genes that show different levels of expression in a comparison of wild-type L2 or L3 larvae (non-dauer) to TGFbeta mutants at similar developmental stages undergoing dauer formation. Many insulin/IGF pathway and other known dauer regulatory genes have changes in expression that suggest strong positive feedback by the TGFbeta pathway. In addition, many insulin-like ligand and novel genes with similarity to the extracellular domain of insulin/IGF receptors have altered expression. We have identified a large group of regulated genes with putative binding sites for the FOXO transcription factor, DAF-16. Genes with DAF-16 sites upstream of the transcription start site tend to be upregulated, whereas genes with DAF-16 sites downstream of the coding region tend to be downregulated. Finally, we also see strong regulation of many novel hedgehog- and patched-related genes, hormone biosynthetic genes, cell cycle genes, and other regulatory genes.

Conclusions: The feedback regulation of insulin/IGF pathway and other dauer genes that we observe would be predicted to amplify signals from the TGFbeta pathway; this amplification may serve to ensure a decisive choice between "dauer" and "non-dauer", even if environmental cues are ambiguous. Up and down regulation of insulin-like ligands and novel genes with similarity to the extracellular domain of insulin/IGF receptors suggests opposing roles for several members of these large gene families. Unlike in adults, most genes with putative DAF-16 binding sites are upregulated during dauer entry, suggesting that DAF-16 has different activity in dauer versus adult metabolism and aging. However, our observation that the position of putative DAF-16 binding sites is correlated with the direction of regulation suggests a novel method of achieving gene-specific regulation from a single pathway. We see evidence of TGFbeta-mediated regulation of several other classes of regulatory genes, and we discuss possible functions of these genes in dauer formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / physiology
  • Animals
  • Binding Sites / physiology
  • Caenorhabditis elegans / embryology
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Caenorhabditis elegans Proteins / physiology
  • Cytochrome P-450 Enzyme System / physiology
  • DNA-Binding Proteins / physiology
  • Drosophila Proteins / physiology
  • Feedback, Physiological / physiology
  • Forkhead Transcription Factors
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / physiology*
  • Genes, Helminth / physiology*
  • Genes, cdc / physiology
  • Hedgehog Proteins
  • Insulin / metabolism
  • Larva / genetics
  • Larva / physiology
  • Membrane Proteins / physiology
  • Oligonucleotide Array Sequence Analysis / methods
  • Receptor, Insulin / physiology
  • Receptors, Cell Surface / physiology
  • Receptors, G-Protein-Coupled / physiology
  • Repressor Proteins / physiology
  • Sequence Homology, Nucleic Acid
  • Signal Transduction / physiology*
  • Smell / genetics
  • Somatomedins / metabolism
  • Trans-Activators / physiology
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Transforming Growth Factor beta / physiology*

Substances

  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Forkhead Transcription Factors
  • Hedgehog Proteins
  • Insulin
  • LIN-28 protein, C elegans
  • LIN-29 protein, C elegans
  • Membrane Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Repressor Proteins
  • Somatomedins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • daf-16 protein, C elegans
  • ptc protein, Drosophila
  • Cytochrome P-450 Enzyme System
  • DAF-2 protein, C elegans
  • Receptor, Insulin