During adverse environmental conditions, C. elegans larvae can enter a diapause-like stage called "dauer", and three parallel signalling pathways are implicated in this decision (insulin-like, TGF-, or cGMP). The dauer larva is specialized for long-term survival, presumably as a result of profound metabolic changes, as well as the establishment and maintenance of cell cycle quiescence throughout the animal, including the cells of the germline. Surprisingly, the Notch ligand (LAG-2) is strongly expressed in the distal tip cells throughout the dauer stage, suggesting that the germ cells presumably receive signals to proliferate, yet they nevertheless arrest without entering the default meiotic program. We reasoned therefore that dauer-inducing signals repress mitosis downstream of the Notch ligand/receptor interaction, while the latter may continue to block entry into meiosis.From a genetic screen designed to identify these potential regulatory genes, we have characterized one mutant (
aak-2) in which the dauer larvae show pronounced germline hyperplasia when induced by either of the three signalling pathways mentioned above. In
glp-1 (Notch receptor) mutants, germ cells enter meiosis prematurely, but arrest in pachytene during dauer. However, in
glp-1;
aak-2 dauer larvae, germ cells enter meiosis and complete spermatogenesis during dauer development, indicating that
aak-2 not only suppresses germ cell mitosis, but also blocks progression through meiosis during dauer development. From our genetic analysis, we found that
daf-18/PTEN and
par-4/LKB1, the loss of which causes cancer in humans (Cowden and Peutz-Jeghers syndromes, respectively), are also required to suppress germline proliferation during dauer formation triggered by either reduced insulin-like or TGF- signalling.A striking, independent phenotype of
aak-2 dauer larvae is that they are short-lived.
aak-2 encodes a C. elegans homolog of the mammalian AMP-activated kinase alpha-2 catalytic subunit, a metabolic "master switch", suggesting that the longevity of the dauer larva may require a substantial metabolic change that is largely triggered by
aak-2. LKB1, is a major activator of AMPK and reduced
par-4 activity partially phenocopies and enhances aak-mediated defects, suggesting that both proteins may cooperate downstream of
daf-18 in insulin-like and TGF- signalling-dependent germline regulation, providing genetic evidence that defective AMPK activation may participate in tumorigenesis in patients affected with Cowden or Peutz-Jeghers syndromes.