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.
Highlights
Sterols are essential in most eukaryotic cells and play a structural role in the architecture of their membranes
The nematode Caenorhabditis elegans provides a valuable model system to study the orchestration of cholesterol metabolism and function at the level of a whole organism
When eggs derived from mothers grown on normal plates (5 lg/ml of cholesterol; approximately 13 lM) hatched at low population densities on sterol-free plates seeded with bacteria, the first generation of worms developed from eggs to adults without external cholesterol
Summary
Sterols are essential in most eukaryotic cells and play a structural role in the architecture of their membranes. Cholesterol, together with glycosphingolipids, is proposed to organise membrane microdomains ( called ‘‘rafts’’), which provide platforms for protein sorting or signal transduction (Simons and Toomre 2000). In addition to this structural role in the membrane, cholesterol is essential for a variety of signalling processes. C. elegans, like other nematodes, cannot synthesise sterols de novo (Hieb and Rothstein 1968; Chitwood 1999) It requires an exogenous source of sterols, which enables (i) analysis of sterol metabolism using labelled precursors and (ii) analysis of sterol functions by feeding normal and mutant worms with cholesterol derivatives and related sterols
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