Inhibition of germline proliferation during C. elegans dauer development requires PTEN, LKB1 and AMPK signalling.
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-beta 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-beta family members, PTEN or LKB1 result in related tumour-predisposing syndromes. Our findings establish a developmental relationship that may underscore their shared, characteristic aetiology.
Narbonne
Patrick
P
Department of Biology, McGill University, 1205 Dr Penfield Avenue, Montréal, Québec H3A 1B1, Canada.
Roy
Richard
R
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D002453:Cell Cycle; D049109:Cell Proliferation; D004625:Embryo, Nonmammalian / Q000502:physiology; D051858:Forkhead Transcription Factors; D005854:Germ Cells / Q000502:physiology*; D007814:Larva; D008136:Longevity; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C108831:daf-16 protein, C elegans; D011494:Protein Kinases; C107483:DAF-2 protein, C elegans; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase