The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin

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Published on: October 19, 2006

Margret H Bülow1, Ruedi Aebersold, Michael J Pankratz

  • 1Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.

Plos One
|January 11, 2011
PubMed

Insights

The transcription factor Forkhead (FKH) regulates organism size downstream of the Target of rapamycin (TOR) signaling pathway. FKH levels and localization are influenced by nutrient availability and TOR activity, impacting growth and gene expression.

Area of Science:

  • Cellular and Molecular Biology
  • Genetics and Genomics
  • Developmental Biology

Background:

  • Forkhead transcription factors (FoxO subfamily) are key regulators of insulin signaling.
  • The role of transcription factors downstream of Target of rapamycin (TOR) signaling in growth control is less understood.
  • Studies in nematodes suggest FoxA transcription factors act downstream of TOR.

Purpose of the Study:

  • To investigate the role of the FoxA protein Forkhead (FKH) in Drosophila.
  • To determine if FKH regulates cellular and organismal size downstream of TOR signaling.
  • To elucidate the relationship between FKH, TOR signaling, and nutrient status.

Main Methods:

  • Ectopic expression and targeted knockdown of FKH in Drosophila larval tissues.
  • Analysis of size phenotypes under varying nutrient conditions and TOR signaling levels.
  • Assessment of FKH protein subcellular localization.
  • Quantitative analysis of target gene expression (CG6770, cabut, d4E-BP).

Main Results:

  • FKH overexpression negatively impacts growth under fed conditions, unaffected by rapamycin.
  • FKH knockdown attenuates size reduction during starvation or low TOR signaling.
  • FKH protein shifts from cytoplasmic to nuclear localization with reduced TOR signaling or rapamycin treatment.
  • Rapamycin and FKH expression induce target genes CG6770 and cabut; FKH knockdown silences them.
  • FKH is required for TOR-mediated growth inhibition and target gene induction.
  • FKH impacts d4E-BP transcription, indicating crosstalk with the insulin pathway.

Conclusions:

  • FKH acts as a crucial mediator of TOR signaling in the regulation of cellular and organismal size in Drosophila.
  • Nutrient status and TOR signaling levels modulate FKH activity and localization.
  • FKH influences the expression of specific target genes involved in growth control.
  • A functional link exists between TOR signaling, FKH, and the insulin pathway via d4E-BP.

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