Cell-nonautonomous signaling of FOXO/DAF-16 to the stem cells of Caenorhabditis elegans

PLoS Genet. 2012;8(8):e1002836. doi: 10.1371/journal.pgen.1002836. Epub 2012 Aug 16.

Abstract

In Caenorhabditis elegans (C. elegans), the promotion of longevity by the transcription factor DAF-16 requires reduced insulin/IGF receptor (IIR) signaling or the ablation of the germline, although the reason for the negative impact of germ cells is unknown. FOXO/DAF-16 activity inhibits germline proliferation in both daf-2 mutants and gld-1 tumors. In contrast to its function as a germline tumor suppressor, we now provide evidence that somatic DAF-16 in the presence of IIR signaling can also result in tumorigenic activity, which counteracts robust lifespan extension. In contrast to the cell-autonomous IIR signaling, which is required for larval germline proliferation, activation of DAF-16 in the hypodermis results in hyperplasia of the germline and disruption of the surrounding basement membrane. SHC-1 adaptor protein and AKT-1 kinase antagonize, whereas AKT-2 and SGK-1 kinases promote, this cell-nonautonomous DAF-16 function. Our data suggest that a functional balance of DAF-16 activities in different tissues determines longevity and reveals a novel, cell-nonautonomous role of FOXO/DAF-16 to affect stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Developmental
  • Germ Cells / cytology
  • Germ Cells / metabolism
  • Humans
  • Longevity / genetics*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism
  • Signal Transduction / genetics*
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Receptors, Somatomedin
  • Shc Signaling Adaptor Proteins
  • Transcription Factors
  • daf-16 protein, C elegans
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sgk-1 protein, C elegans
  • akt-1 protein, C elegans
  • akt-2 protein, C elegans

Grant support

This work was funded through German Research Foundation (DFG) Collaborative Research Centres (CRC) 746 and 850, European Union Network of Excellence LIFESPAN, and the German Research Foundation (DFG) Excellence Initiative (FRIAS LIFENET and BIOSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.