Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans

Donha Park, Karen L. Jones, Hyojin Lee, Terrance P. Snutch, Stefan Taubert, Donald L. Riddle

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Transforming growth factor β (TGF-β) signaling acts through Smad proteins to play fundamental roles in cell proliferation, differentiation, apoptosis, and metabolism. The Receptor associated Smads (R-Smads) interact with DNA and other nuclear proteins to regulate target gene transcription. Here, we demonstrate that the Caenorhabditis elegans R-Smad DAF-8 partners with the nuclear hormone receptor NHR-69, a C. elegans ortholog of mammalian hepatocyte nuclear factor 4α HNF4α), to repress the exp-2 potassium channel gene and increase insulin secretion. We find that NHR-69 associates with DAF-8 both in vivo and in vitro. Functionally, daf-8 nhr-69 double mutants show defects in neuropeptide secretion and phenotypes consistent with reduced insulin signaling such as increased expression of the sod-3 and gst-10 genes and a longer life span. Expression of the exp-2 gene, encoding a voltage-gated potassium channel, is synergistically increased in daf-8 nhr-69 mutants compared to single mutants and wild-type worms. In turn, exp-2 acts selectively in the ASI neurons to repress the secretion of the insulin-like peptide DAF-28. Importantly, exp-2 mutation shortens the long life span of daf-8 nhr-69 double mutants, demonstrating that exp-2 is required downstream of DAF-8 and NHR-69. Finally, animals over-expressing NHR-69 specifically in DAF-28-secreting ASI neurons exhibit a lethargic, hypoglycemic phenotype that is rescued by exogenous glucose. We propose a model whereby DAF-8/R-Smad and NHR-69 negatively regulate the transcription of exp-2 to promote neuronal DAF-28 secretion, thus demonstrating a physiological crosstalk between TGF-β and HNF4α-like signaling in C. elegans. NHR-69 and DAF-8 dependent regulation of exp-2 and DAF-28 also provides a novel molecular mechanism that contributes to the previously recognized link between insulin and TGF-β signaling in C. elegans.

Original languageEnglish
Article numbere1002519
JournalPLoS Genetics
Volume8
Issue number2
DOIs
Publication statusPublished - 2012 Feb 1

Fingerprint

transforming growth factors
Potassium Channels
potassium channels
hormone receptors
Caenorhabditis elegans
Transforming Growth Factors
Cytoplasmic and Nuclear Receptors
secretion
hormone
insulin
potassium
Insulin
mutants
gene
insulin secretion
Genes
phenotype
Hepatocyte Nuclear Factor 4
genes
transcription (genetics)

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Park, Donha ; Jones, Karen L. ; Lee, Hyojin ; Snutch, Terrance P. ; Taubert, Stefan ; Riddle, Donald L. / Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans. In: PLoS Genetics. 2012 ; Vol. 8, No. 2.
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Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans. / Park, Donha; Jones, Karen L.; Lee, Hyojin; Snutch, Terrance P.; Taubert, Stefan; Riddle, Donald L.

In: PLoS Genetics, Vol. 8, No. 2, e1002519, 01.02.2012.

Research output: Contribution to journalArticle

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T1 - Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans

AU - Park, Donha

AU - Jones, Karen L.

AU - Lee, Hyojin

AU - Snutch, Terrance P.

AU - Taubert, Stefan

AU - Riddle, Donald L.

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AB - Transforming growth factor β (TGF-β) signaling acts through Smad proteins to play fundamental roles in cell proliferation, differentiation, apoptosis, and metabolism. The Receptor associated Smads (R-Smads) interact with DNA and other nuclear proteins to regulate target gene transcription. Here, we demonstrate that the Caenorhabditis elegans R-Smad DAF-8 partners with the nuclear hormone receptor NHR-69, a C. elegans ortholog of mammalian hepatocyte nuclear factor 4α HNF4α), to repress the exp-2 potassium channel gene and increase insulin secretion. We find that NHR-69 associates with DAF-8 both in vivo and in vitro. Functionally, daf-8 nhr-69 double mutants show defects in neuropeptide secretion and phenotypes consistent with reduced insulin signaling such as increased expression of the sod-3 and gst-10 genes and a longer life span. Expression of the exp-2 gene, encoding a voltage-gated potassium channel, is synergistically increased in daf-8 nhr-69 mutants compared to single mutants and wild-type worms. In turn, exp-2 acts selectively in the ASI neurons to repress the secretion of the insulin-like peptide DAF-28. Importantly, exp-2 mutation shortens the long life span of daf-8 nhr-69 double mutants, demonstrating that exp-2 is required downstream of DAF-8 and NHR-69. Finally, animals over-expressing NHR-69 specifically in DAF-28-secreting ASI neurons exhibit a lethargic, hypoglycemic phenotype that is rescued by exogenous glucose. We propose a model whereby DAF-8/R-Smad and NHR-69 negatively regulate the transcription of exp-2 to promote neuronal DAF-28 secretion, thus demonstrating a physiological crosstalk between TGF-β and HNF4α-like signaling in C. elegans. NHR-69 and DAF-8 dependent regulation of exp-2 and DAF-28 also provides a novel molecular mechanism that contributes to the previously recognized link between insulin and TGF-β signaling in C. elegans.

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