Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal.


:The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.






Yan KS,Janda CY,Chang J,Zheng GXY,Larkin KA,Luca VC,Chia LA,Mah AT,Han A,Terry JM,Ootani A,Roelf K,Lee M,Yuan J,Li X,Bolen CR,Wilhelmy J,Davies PS,Ueno H,von Furstenberg RJ,Belgrader P,Ziraldo SB,Ordonez H,H




Has Abstract


2017-05-11 00:00:00
















  • Geometry-induced electrostatic trapping of nanometric objects in a fluid.

    abstract::The ability to trap an object-whether a single atom or a macroscopic entity-affects fields as diverse as quantum optics, soft condensed-matter physics, biophysics and clinical medicine. Many sophisticated methodologies have been developed to counter the randomizing effect of Brownian motion in solution, but stable tra...


    pub_type: 杂志文章


    authors: Krishnan M,Mojarad N,Kukura P,Sandoghdar V

    更新日期:2010-10-07 00:00:00

  • El Niño-Southern Oscillation complexity.

    abstract::El Niño events are characterized by surface warming of the tropical Pacific Ocean and weakening of equatorial trade winds that occur every few years. Such conditions are accompanied by changes in atmospheric and oceanic circulation, affecting global climate, marine and terrestrial ecosystems, fisheries and human activ...


    pub_type: 杂志文章,评审


    authors: Timmermann A,An SI,Kug JS,Jin FF,Cai W,Capotondi A,Cobb KM,Lengaigne M,McPhaden MJ,Stuecker MF,Stein K,Wittenberg AT,Yun KS,Bayr T,Chen HC,Chikamoto Y,Dewitte B,Dommenget D,Grothe P,Guilyardi E,Ham YG,Hayashi M

    更新日期:2018-07-01 00:00:00

  • Visual but not trigeminal mediation of magnetic compass information in a migratory bird.

    abstract::Magnetic compass information has a key role in bird orientation, but the physiological mechanisms enabling birds to sense the Earth's magnetic field remain one of the unresolved mysteries in biology. Two biophysical mechanisms have become established as the most promising magnetodetection candidates. The iron-mineral-...


    pub_type: 杂志文章


    authors: Zapka M,Heyers D,Hein CM,Engels S,Schneider NL,Hans J,Weiler S,Dreyer D,Kishkinev D,Wild JM,Mouritsen H

    更新日期:2009-10-29 00:00:00

  • Central reorganization of sensory pathways following peripheral nerve regeneration in fetal monkeys.

    abstract::Transection of a sensory nerve in adults results in profound abnormalities in sensory perception, even if the severed nerve is surgically repaired to facilitate accurate nerve regeneration. In marked contrast, fewer perceptual errors follow nerve transection and surgical repair in children. The basis for this superior...


    pub_type: 杂志文章


    authors: Florence SL,Jain N,Pospichal MW,Beck PD,Sly DL,Kaas JH

    更新日期:1996-05-02 00:00:00

  • Building C(sp3)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

    abstract::Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to syn...


    pub_type: 杂志文章


    authors: Chen TG,Barton LM,Lin Y,Tsien J,Kossler D,Bastida I,Asai S,Bi C,Chen JS,Shan M,Fang H,Fang FG,Choi HW,Hawkins L,Qin T,Baran PS

    更新日期:2018-08-01 00:00:00

  • Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.

    abstract::Human B cell stimulatory factor 2 (BSF-2) was originally characterized and isolated as a T cell-derived factor that caused the terminal maturation of activated B cells to immunoglobulin-producing cells. Molecular cloning of the complementary DNA predicts that BSF-2 is a protein of relative molecular mass (Mr) 26,000 s...


    pub_type: 杂志文章


    authors: Kawano M,Hirano T,Matsuda T,Taga T,Horii Y,Iwato K,Asaoku H,Tang B,Tanabe O,Tanaka H

    更新日期:1988-03-03 00:00:00

  • Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2).

    abstract::The human T cell erythrocyte receptor (CD2 antigen) allows thymocytes and mature T cells to adhere to thymic epithelium and target cells through a cell surface protein, LFA-3 (refs 1-6). Monoclonal antibodies recognizing CD2 can either block adhesion or, in certain combinations, induce an antigen-independent T cell ac...


    pub_type: 杂志文章


    authors: Peterson A,Seed B

    更新日期:1987-10-29 00:00:00

  • Kondo effect in an integer-spin quantum dot

    abstract::The Kondo effect--a many-body phenomenon in condensed-matter physics involving the interaction between a localized spin and free electrons--was discovered in metals containing small amounts of magnetic impurities, although it is now recognized to be of fundamental importance in a wide class of correlated electron syst...


    pub_type: 杂志文章


    authors: Sasaki S,De Franceschi S,Elzerman JM,van der Wiel WG,Eto M,Tarucha S,Kouwenhoven LP

    更新日期:2000-06-15 00:00:00

  • Decarboxylative alkenylation.

    abstract::Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Her...


    pub_type: 杂志文章


    authors: Edwards JT,Merchant RR,McClymont KS,Knouse KW,Qin T,Malins LR,Vokits B,Shaw SA,Bao DH,Wei FL,Zhou T,Eastgate MD,Baran PS

    更新日期:2017-05-11 00:00:00

  • Global reference mapping of human transcription factor footprints.

    abstract::Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I foot...


    pub_type: 杂志文章


    authors: Vierstra J,Lazar J,Sandstrom R,Halow J,Lee K,Bates D,Diegel M,Dunn D,Neri F,Haugen E,Rynes E,Reynolds A,Nelson J,Johnson A,Frerker M,Buckley M,Kaul R,Meuleman W,Stamatoyannopoulos JA

    更新日期:2020-07-01 00:00:00

  • Nucleotide sequence of avian retroviral oncogene v-mil: homologue of murine retroviral oncogene v-raf.

    abstract::Eukaryotic cells contain genes termed proto-oncogenes (c-onc) which have the potential to transform cells in culture and induce tumours in vivo. Most of these genes have been identified by their occasional incorporation into retroviral genomes which can act as natural transducing vectors for these and perhaps other ce...


    pub_type: 杂志文章


    authors: Sutrave P,Bonner TI,Rapp UR,Jansen HW,Patschinsky T,Bister K

    更新日期:1984-05-03 00:00:00

  • Pressure sensitivity of olivine slip systems and seismic anisotropy of Earth's upper mantle.

    abstract::The mineral olivine dominates the composition of the Earth's upper mantle and hence controls its mechanical behaviour and seismic anisotropy. Experiments at high temperature and moderate pressure, and extensive data on naturally deformed mantle rocks, have led to the conclusion that olivine at upper-mantle conditions ...


    pub_type: 杂志文章


    authors: Mainprice D,Tommasi A,Couvy H,Cordier P,Frost DJ

    更新日期:2005-02-17 00:00:00

  • Directional guidance of neuronal migration in the olfactory system by the protein Slit.

    abstract::Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration have remained unclear. Here we report that the secreted protein Slit repels neuronal precursors migrating from the anterior subventricular zone in the telencephalon to the olfactory bulb. Our results provide a di...


    pub_type: 杂志文章


    authors: Wu W,Wong K,Chen J,Jiang Z,Dupuis S,Wu JY,Rao Y

    更新日期:1999-07-22 00:00:00

  • Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.

    abstract::Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 ...


    pub_type: 杂志文章


    authors: Rodgers JT,Lerin C,Haas W,Gygi SP,Spiegelman BM,Puigserver P

    更新日期:2005-03-03 00:00:00

  • Cytotoxic T lymphocyte recognition of transfected cells expressing a cloned retroviral gene.

    abstract::The lysis of murine sarcoma virus-murine leukaemia virus (MSV-MuLV)-induced tumour cells by cytotoxic T lymphocytes (CTL) appears to require that an antigen specified by MSV-MuLV, or induced by the infection, be presented in association with class I major histocompatibility complex antigens. The viral proteins of the ...


    pub_type: 杂志文章


    authors: Flyer DC,Burakoff SJ,Faller DV

    更新日期:1983-10-27 00:00:00

  • Do female hyaenas choose mates based on tenure?

    abstract::In their investigation into whether female mate-choice drives male dispersal, Höner et al. argue that female spotted hyaenas (Crocuta crocuta) prefer mates whose tenure in the social group is less than the females' age, to avoid paternal incest, and suggest that male dispersal reflects this preference. However, we are...


    pub_type: 评论,杂志文章


    authors: Van Horn RC,Watts HE,Holekamp KE

    更新日期:2008-07-10 00:00:00

  • Structure and function of the 5'-->3' exoribonuclease Rat1 and its activating partner Rai1.

    abstract::The 5'-->3' exoribonucleases (XRNs) comprise a large family of conserved enzymes in eukaryotes with crucial functions in RNA metabolism and RNA interference. XRN2, or Rat1 in yeast, functions primarily in the nucleus and also has an important role in transcription termination by RNA polymerase II (refs 7-14). Rat1 exo...


    pub_type: 杂志文章


    authors: Xiang S,Cooper-Morgan A,Jiao X,Kiledjian M,Manley JL,Tong L

    更新日期:2009-04-09 00:00:00

  • Observation of coherent optical information storage in an atomic medium using halted light pulses.

    abstract::Electromagnetically induced transparency is a quantum interference effect that permits the propagation of light through an otherwise opaque atomic medium; a 'coupling' laser is used to create the interference necessary to allow the transmission of resonant pulses from a 'probe' laser. This technique has been used to s...


    pub_type: 杂志文章


    authors: Liu C,Dutton Z,Behroozi CH,Hau LV

    更新日期:2001-01-25 00:00:00

  • Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels.

    abstract::Haem is essential for living organisms, functioning as a crucial element in the redox-sensitive reaction centre in haemproteins. During the biogenesis of these proteins, the haem cofactor is typically incorporated enzymatically into the haem pockets of the apo-haemprotein as the functionally indispensable prosthetic g...


    pub_type: 杂志文章


    authors: Tang XD,Xu R,Reynolds MF,Garcia ML,Heinemann SH,Hoshi T

    更新日期:2003-10-02 00:00:00

  • Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis.

    abstract::A major component of the large genomes of higher plants and vertebrates comprises transposable elements and their derivatives, which potentially reduce the stability of the genome. It has been proposed that methylation of cytosine residues may suppress transposition, but experimental evidence for this has been limited...


    pub_type: 杂志文章


    authors: Miura A,Yonebayashi S,Watanabe K,Toyama T,Shimada H,Kakutani T

    更新日期:2001-05-10 00:00:00

  • P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1.

    abstract::The factors determining disease severity in malaria are complex and include host polymorphisms, acquired immunity and parasite virulence. Studies in Africa have shown that severe malaria is associated with the ability of erythrocytes infected with the parasite Plasmodium falciparum to bind uninfected erythrocytes and ...


    pub_type: 杂志文章


    authors: Rowe JA,Moulds JM,Newbold CI,Miller LH

    更新日期:1997-07-17 00:00:00

  • Transcript-RNA-templated DNA recombination and repair.

    abstract::Homologous recombination is a molecular process that has multiple important roles in DNA metabolism, both for DNA repair and genetic variation in all forms of life. Generally, homologous recombination involves the exchange of genetic information between two identical or nearly identical DNA molecules; however, homolog...


    pub_type: 杂志文章


    authors: Keskin H,Shen Y,Huang F,Patel M,Yang T,Ashley K,Mazin AV,Storici F

    更新日期:2014-11-20 00:00:00

  • Antigen presentation enhanced by the alternatively spliced invariant chain gene product p41.

    abstract::During biosynthesis, class II molecules of the major histocompatibility complex are associated with a nonpolymorphic protein called invariant chain, Ii, which facilitates folding of class II molecules and their exit from the endoplasmic reticulum, interferes with their association with peptide and directs their post-G...


    pub_type: 杂志文章


    authors: Peterson M,Miller J

    更新日期:1992-06-18 00:00:00

  • Elevated CO2 increases productivity and invasive species success in an arid ecosystem.

    abstract::Arid ecosystems, which occupy about 20% of the earth's terrestrial surface area, have been predicted to be one of the most responsive ecosystem types to elevated atmospheric CO2 and associated global climate change. Here we show, using free-air CO2 enrichment (FACE) technology in an intact Mojave Desert ecosystem, tha...


    pub_type: 杂志文章


    authors: Smith SD,Huxman TE,Zitzer SF,Charlet TN,Housman DC,Coleman JS,Fenstermaker LK,Seemann JR,Nowak RS

    更新日期:2000-11-02 00:00:00

  • Structural relaxation in supercooled water by time-resolved spectroscopy.

    abstract::Water has many kinetic and thermodynamic properties that exhibit an anomalous dependence on temperature, in particular in the supercooled phase. These anomalies have long been interpreted in terms of underlying structural causes, and their experimental characterization points to the existence of a singularity at a tem...


    pub_type: 杂志文章


    authors: Torre R,Bartolini P,Righini R

    更新日期:2004-03-18 00:00:00

  • Dynamics of nucleosome remodelling by individual ACF complexes.

    abstract::The ATP-dependent chromatin assembly and remodelling factor (ACF) functions to generate regularly spaced nucleosomes, which are required for heritable gene silencing. The mechanism by which ACF mobilizes nucleosomes remains poorly understood. Here we report a single-molecule FRET study that monitors the remodelling of...


    pub_type: 杂志文章


    authors: Blosser TR,Yang JG,Stone MD,Narlikar GJ,Zhuang X

    更新日期:2009-12-24 00:00:00

  • Structural basis of highly conserved ribosome recycling in eukaryotes and archaea.

    abstract::Ribosome-driven protein biosynthesis is comprised of four phases: initiation, elongation, termination and recycling. In bacteria, ribosome recycling requires ribosome recycling factor and elongation factor G, and several structures of bacterial recycling complexes have been determined. In the eukaryotic and archaeal k...


    pub_type: 杂志文章


    authors: Becker T,Franckenberg S,Wickles S,Shoemaker CJ,Anger AM,Armache JP,Sieber H,Ungewickell C,Berninghausen O,Daberkow I,Karcher A,Thomm M,Hopfner KP,Green R,Beckmann R

    更新日期:2012-02-22 00:00:00

  • An anti-glitch in a magnetar.

    abstract::Magnetars are neutron stars with X-ray and soft γ-ray outbursts thought to be powered by intense internal magnetic fields. Like conventional neutron stars in the form of radio pulsars, magnetars exhibit 'glitches' during which angular momentum is believed to be transferred between the solid outer crust and the superfl...


    pub_type: 杂志文章


    authors: Archibald RF,Kaspi VM,Ng CY,Gourgouliatos KN,Tsang D,Scholz P,Beardmore AP,Gehrels N,Kennea JA

    更新日期:2013-05-30 00:00:00

  • Peripheral deletion of antigen-reactive T cells in oral tolerance.

    abstract::Oral administration of antigen is used to induce antigen-specific peripheral immune tolerance. As well as preventing systemic immune responses to ingested proteins, oral tolerance to autoantigens has also been used to suppress autoimmune diseases in animals and humans. Both active suppression and clonal anergy are sug...


    pub_type: 杂志文章


    authors: Chen Y,Inobe J,Marks R,Gonnella P,Kuchroo VK,Weiner HL

    更新日期:1995-07-13 00:00:00

  • Nuclear weapons: US research put to vote.

    abstract::A statute banning nuclear weapons research in Cambridge, Massachusetts, is scheduled for a referendum vote in November 1983. If passed, the act would require the city to fine or imprison violators after the ban takes effect in October 1985, and could have an impact on work done at Harvard University and the Massachus...


    pub_type: 新闻


    authors: David P

    更新日期:1983-09-15 00:00:00