title: S6K links cell fate, cell cycle and nutrient response in C. elegans germline stem/progenitor cells.
abstract: Coupling of stem/progenitor cell proliferation and differentiation to organismal physiological demands ensures the proper growth and homeostasis of tissues. However, in vivo mechanisms underlying this control are poorly characterized. We investigated the role of ribosomal protein S6 kinase (S6K) at the intersection of nutrition and the establishment of a stem/progenitor cell population using the C. elegans germ line as a model. We find that rsks-1 (which encodes the worm homolog of mammalian p70S6K) is required germline-autonomously for proper establishment of the germline progenitor pool. In the germ line, rsks-1 promotes cell cycle progression and inhibits larval progenitor differentiation, promotes growth of adult tumors and requires a conserved TOR phosphorylation site. Loss of rsks-1 and ife-1 (eIF4E) together reduces the germline progenitor pool more severely than either single mutant and similarly to reducing the activity of let-363 (TOR) or daf-15 (RAPTOR). Moreover, rsks-1 acts in parallel with the glp-1 (Notch) and daf-2 (insulin-IGF receptor) pathways, and does not share the same genetic dependencies with its role in lifespan control. We show that overall dietary restriction and amino acid deprivation cause germline defects similar to a subset of rsks-1 mutant phenotypes. Consistent with a link between diet and germline proliferation via rsks-1, loss of rsks-1 renders the germ line largely insensitive to the effects of dietary restriction. Our studies establish the C. elegans germ line as an in vivo model to understand TOR-S6K signaling in proliferation and differentiation and suggest that this pathway is a key nutrient-responsive regulator of germline progenitors.
authors.affiliation: Developmental Genetics Program, Helen and Martin Kimmel Center for Stem Cell Biology, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Dorota Z
authors.initials: DZ
authors.lastname: Korta
authors.forename: Simon
authors.initials: S
authors.lastname: Tuck
authors.forename: E Jane Albert
authors.initials: EJ
authors.lastname: Hubbard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D004032:Diet; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D039642:Eukaryotic Initiation Factors; C060620:Glp-1 protein, C elegans; C558781:IFE-1 protein, C elegans; D008562:Membrane Glycoproteins; D051880:Receptors, Notch; D017853:Phosphotransferases (Alcohol Group Acceptor); C472494:let-363 protein, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C571892:Rsks-1 protein, C elegans