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.
Article: Deletion of the intestinal peptide transporter affects insulin and TOR signaling in Caenorhabditis elegans.[show abstract] [hide abstract]
ABSTRACT: The mammalian intestinal peptide transporter PEPT1 mediates the uptake of di- and tripeptides from the gut lumen into intestinal epithelial cells and acts in parallel with amino acid transporters. Here we address the importance of the PEPT1 orthologue PEP-2 for the assimilation of dietary protein and for overall protein nutrition in Caenorhabditis elegans. pep-2 is expressed specifically along the apical membrane of the intestinal cells, and in pep-2 deletion mutant animals, uptake of intact peptides from the gut lumen is abolished. The consequences are a severely retarded development, reduced progeny and body size, and increased stress tolerance. We show here that pep-2 cross-talks with both the C. elegans target of rapamycin (TOR) and the DAF-2/insulin-signaling pathways. The pep-2 mutant enhances the developmental and longevity phenotypes of daf-2, resulting, among other effects, in a pronounced increase in adult life span. Moreover, all aspects of a weak let-363/TOR RNA interference phenotype are intensified by pep-2 deletion, indicating that pep-2 function upstream of TOR-mediated nutrient sensing. Our findings provide evidence for a predominant role of the intestinal peptide transporter for the delivery of bulk quantities of amino acids for growth and development, which consequently affects signaling pathways that regulate metabolism and aging.Journal of Biological Chemistry 09/2004; 279(35):36739-45. · 4.77 Impact Factor
Article: The particles of the embryonic cerebrospinal fluid: how could they influence brain development?[show abstract] [hide abstract]
ABSTRACT: During brain development, the embryonic cerebrospinal fluid (E-CSF) allows brain expansion and promotes neuroepithelial cell survival, proliferation or differentiation. Previous analyses of E-CSF content have revealed a high protein concentration and the presence of membranous particles. The role of these particles in the E-CSF remains poorly investigated. In this study we showed that the E-CSF contains at least two pools of particles: lipoproteins and exosome-like particles. We showed that these two populations of particles strongly interact with neuropithelial cells via an endocytic process, which display regional specificity along the developing neural tube. Finally, we explore and discuss the possibility that these interactions may influence brain development through the regulation of morphogen and growth factor signaling transduction.Brain Research Bulletin 04/2008; 75(2-4):289-94. · 2.82 Impact Factor
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ABSTRACT: The germ line of the nematode Caenorhabditis elegans influences life-span; when the germ-line precursor cells are removed, life-span is increased dramatically. We find that neither sperm, nor oocytes, nor meiotic precursor cells are responsible for this effect. Rather life-span is influenced by the proliferating germ-line stem cells. These cells, as well as a downstream transcriptional regulator, act in the adult to influence aging, indicating that the aging process remains plastic during adulthood. We propose that the germ-line stem cells affect life-span by influencing the production of, or the response to, a steroid hormone that promotes longevity.Science 02/2002; 295(5554):502-5. · 31.20 Impact Factor