Sterol-Derived Hormone(s) Controls Entry into Diapause in Caenorhabditis elegans by Consecutive Activation of DAF-12 and DAF-16

Abstract

Upon starvation or overcrowding, Caenorhabditis elegans interrupts its reproductive cycle and forms a specialised larva called dauer (enduring). This process is regulated by TGF-β and insulin-signalling pathways and is connected with the control of life span through the insulin pathway components DAF-2 and DAF-16. We found that replacing cholesterol with its methylated metabolite lophenol induced worms to form dauer larvae in the presence of food and low population density. Our data indicate that methylated sterols do not actively induce the dauer formation but rather that the reproductive growth requires a cholesterol-derived hormone that cannot be produced from methylated sterols. Using the effect of lophenol on growth, we have partially purified activity, named gamravali, which promotes the reproduction. In addition, the effect of lophenol allowed us to determine the role of sterols during dauer larva formation and longevity. In the absence of gamravali, the nuclear hormone receptor DAF-12 is activated and thereby initiates the dauer formation program. Active DAF-12 triggers in neurons the nuclear import of DAF-16, a forkhead domain transcription factor that contributes to dauer differentiation. This hormonal control of DAF-16 activation is, however, independent of insulin signalling and has no influence on life span.

Integration of carbohydrate metabolism and redox state controls dauer larva formation in Caenorhabditis elegans

“…Second, DDtps could not suppress the induction of wild-type dauers on substitution of cholesterol by lophenol. As previously shown, DA cannot be produced when lophenol is the only dietary sterol because cholesterol, the precursor for DA synthesis, is absent 25 . DDtps formed dauer larvae on lophenol and this process was not decreased by starvation (Fig.…”

“…24). Conversely, activation of DAF-12 caused by mutation of daf-9 or substitution of the dietary cholesterol with lophenol also induces the formation of arrested dauer-like larvae in daf-16 loss-of-function mutants 25,35 .…”

Alternate metabolism during the dauer stage of the nematode Caenorhabditis elegans

“…Identified pathways regulating this decision include insulin/ IGF-1, TGF-b and cyclic GMP signalling. These signal transduction pathways converge on DAF-9, a cytochrome P450 steroid hydroxylase which is postulated to produce a cholestrol-derived hormone (Gerish and Antebi, 2004;Matyash et al, 2004). The target of this putative hormone is the nuclear hormone receptor DAF-12.…”

Cholesterol-Responsive Metabolic Proteins Are Required for Larval Development in Caenorhabditis elegans

“…Reduction of SAMS-1 and PMT-2 should reduce methylation levels of their substrates in worms grown in CS. It was reported that cholesterol depletion caused accumulation of methylated sterols (Matyash et al, 2004). This finding suggests that SAMS-1 and PMT-2 are not involved in sterol methylation because their levels were decreased in CS.…”