Inhibition of germline proliferation duringC. elegansdauer development requires PTEN, LKB1 and AMPK signalling

Abstract

In C. elegans, reduced insulin-like signalling induces developmental quiescence, reproductive delay and lifespan extension. We show here that the C. elegans orthologues of LKB1 and AMPK cooperate during conditions of reduced insulin-like signalling to establish cell cycle quiescence in the germline stem cell population, in addition to prolonging lifespan. The inactivation of either protein causes aberrant germline proliferation during diapause-like 'dauer' development, whereas the loss of AMPK uncouples developmental arrest from lifespan extension. Reduced TGF-␤ activity also triggers developmental quiescence independent of the insulin-like pathway. Our data suggest that these two signalling pathways converge on the C. elegans PTEN orthologue to coordinate germline proliferation with somatic development during dauer formation, via the regulation of AMPK and its upstream activator LKB1, rather than through the canonical insulin-like signalling cascade. In humans, germline mutations in TGF-␤ family members, PTEN or LKB1 result in related tumour-predisposing syndromes. Our findings establish a developmental relationship that may underscore their shared, characteristic aetiology.

AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

“…This is most notable during the L1 diapause stage and during an alternative postembryonic developmental stage called dauer, where it has been shown to affect germ-line stem cell quiescence, dauer maintenance, and survival (21)(22)(23). Mutations in the C. elegans tumor-suppressor ortholog PTEN/daf-18 cause similar defects in both dauer and L1 diapause-arrested larvae, although it most probably acts through a genetically independent pathway (15,24,25).…”

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

“…AAK-2 is required for life-span extension in response to treatment with the plant product resveratrol, and to some but not all protocols of dietary restriction (Greer et al 2007;Greer and Brunet 2009). It is also required for the arrest of germ cell development that occurs on dietary restriction (Narbonne and Roy 2006), and for inhibition of triglyceride breakdown when worms enter the long-lived Dauer larval form (Narbonne and Roy 2009). Thus, C. elegans AMPK is involved in coupling the availability of nutrients to development and sexual maturation.…”

LKB1; linking cell structure and tumor suppression

“…Liver-specific Lkb1 deletion also causes metabolic defects and loss of activity of AMPK and increased mTOR signaling (Shaw et al, 2005). C. elegans LKB1/Par-4 and AMPK/aak-2 are required for lifespan extension under conditions of energy stress (Narbonne and Roy, 2006). More recently AMPK has been shown to be critical for cellular polarity and tight junction assembly (see below 'Polarity; AMPK-dependent mechanisms and links to energy stress').…”