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.
Development. 2012 Mar;139(5):859-70. doi: 10.1242/dev.074047. Epub 2012 Jan 25.
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.
干细胞/祖细胞的增殖和分化与机体生理需求相偶联，以确保组织的正常生长和稳态。然而，这种调控的体内机制还知之甚少。我们使用秀丽隐杆线虫的生殖系作为模型，研究了核糖体蛋白 S6 激酶（S6K）在营养和建立干细胞/祖细胞群体中的作用。我们发现 rsks-1（编码哺乳动物 p70S6K 的同源物）在生殖系自主建立生殖系祖细胞库中是必需的。在生殖系中，rsks-1 促进细胞周期进程并抑制幼虫祖细胞分化，促进成年肿瘤生长并需要保守的 TOR 磷酸化位点。rsks-1 和 ife-1（eIF4E）的缺失比单一突变体更严重地减少生殖系祖细胞库，与降低 let-363（TOR）或 daf-15（RAPTOR）的活性相似。此外，rsks-1 与 glp-1（Notch）和 daf-2（胰岛素/IGF 受体）途径平行作用，并且与它在寿命控制中的作用没有相同的遗传依赖性。我们表明，总体饮食限制和氨基酸剥夺会导致与 rsks-1 突变体表型的一部分相似的生殖系缺陷。rsks-1 通过饮食与生殖系增殖之间的联系相一致，rsks-1 的缺失使生殖系对饮食限制的影响基本不敏感。我们的研究确立了秀丽隐杆线虫的生殖系作为一种体内模型，以了解增殖和分化中的 TOR-S6K 信号转导，并表明该途径是生殖系祖细胞的关键营养响应调节剂。
