title: Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans.
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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada. dpark@cmmt.ubc.ca
authors.forename: Donha
authors.initials: D
authors.lastname: Park
authors.forename: Karen L
authors.initials: KL
authors.lastname: Jones
authors.forename: Hyojin
authors.initials: H
authors.lastname: Lee
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.forename: Stefan
authors.initials: S
authors.lastname: Taubert
authors.forename: Donald L
authors.initials: DL
authors.lastname: Riddle
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D061385:Insulins; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D061385:Insulins; C578368:NHR-69 protein, C elegans; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018160:Receptors, Cytoplasmic and Nuclear; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C473608:daf-28 protein, C elegans; C403529:exp-2 protein, C elegans; D011972:Receptor, Insulin