Hans Clevers

Summary

Publications

  1. doi request reprint Wnt/β-catenin signaling and disease
    Hans Clevers
    Hubrecht Institute, KNAW and University Medical Center Utrecht, The Netherlands
    Cell 149:1192-205. 2012
  2. pmc Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis
    Meritxell Huch
    Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands
    EMBO J 32:2708-21. 2013
  3. pmc Generation of BAC transgenic epithelial organoids
    Gerald Schwank
    Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    PLoS ONE 8:e76871. 2013
  4. pmc The R-spondin protein family
    Wim B M de Lau
    Hubrecht Institute, Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, The Netherlands
    Genome Biol 13:242. 2012
  5. doi request reprint The intestinal crypt, a prototype stem cell compartment
    Hans Clevers
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands
    Cell 154:274-84. 2013
  6. doi request reprint Paneth cells: maestros of the small intestinal crypts
    Hans C Clevers
    Hubrecht Institute KNAW, University Medical Center Utrecht, Uppsalalaan, Utrecht 3584CT, The Netherlands
    Annu Rev Physiol 75:289-311. 2013
  7. doi request reprint The cancer stem cell: premises, promises and challenges
    Hans Clevers
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands
    Nat Med 17:313-9. 2011
  8. ncbi request reprint Eyeing up new Wnt pathway players
    Hans Clevers
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Cell 139:227-9. 2009
  9. doi request reprint The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium
    Alex Gregorieff
    Hubrecht Institute, Utrecht, The Netherlands
    Gastroenterology 137:1333-45.e1-3. 2009
  10. doi request reprint Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro
    Nick Barker
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht and University Medical Centre Utrecht, Netherlands
    Cell Stem Cell 6:25-36. 2010

Detail Information

Publications83

  1. doi request reprint Wnt/β-catenin signaling and disease
    Hans Clevers
    Hubrecht Institute, KNAW and University Medical Center Utrecht, The Netherlands
    Cell 149:1192-205. 2012
    ..In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future...
  2. pmc Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis
    Meritxell Huch
    Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands
    EMBO J 32:2708-21. 2013
    ..Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality. ..
  3. pmc Generation of BAC transgenic epithelial organoids
    Gerald Schwank
    Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    PLoS ONE 8:e76871. 2013
    ..Here we present a transfection protocol that enables the generation of recombinant mouse and human reporter organoids using BAC (bacterial artificial chromosome) technology. ..
  4. pmc The R-spondin protein family
    Wim B M de Lau
    Hubrecht Institute, Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, The Netherlands
    Genome Biol 13:242. 2012
    ..Lgr5 and Lgr6 are markers for adult stem cells. Because R-spondins are potent stimulators of adult stem cell proliferation in vivo and in vitro, these findings might guide the therapeutic use of R-spondins in regenerative medicine...
  5. doi request reprint The intestinal crypt, a prototype stem cell compartment
    Hans Clevers
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands
    Cell 154:274-84. 2013
    ..These studies are filling in the outlines of a robust homeostatic self-renewal process that defies some of the classical definitions of stem cell behavior, such as asymmetric division, quiescence, and exhaustion. ..
  6. doi request reprint Paneth cells: maestros of the small intestinal crypts
    Hans C Clevers
    Hubrecht Institute KNAW, University Medical Center Utrecht, Uppsalalaan, Utrecht 3584CT, The Netherlands
    Annu Rev Physiol 75:289-311. 2013
    ..Dysfunction of Paneth cell biology contributes to the pathogenesis of chronic inflammatory bowel disease...
  7. doi request reprint The cancer stem cell: premises, promises and challenges
    Hans Clevers
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands
    Nat Med 17:313-9. 2011
    ..This review attempts to summarize the underlying concepts of this notion, to distinguish hard facts from beliefs and to define the future challenges of the field...
  8. ncbi request reprint Eyeing up new Wnt pathway players
    Hans Clevers
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Cell 139:227-9. 2009
    ..In this issue, Ye et al. (2009) and Junge et al. (2009) reveal how an unusual Wnt receptor-ligand complex associated with a spectrum of retinal diseases instructs vascular development in the retina...
  9. doi request reprint The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium
    Alex Gregorieff
    Hubrecht Institute, Utrecht, The Netherlands
    Gastroenterology 137:1333-45.e1-3. 2009
    ..In this study, we investigated the role of the Wnt-responsive, Ets-domain transcription factor Spdef in the differentiation of goblet and Paneth cells...
  10. doi request reprint Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro
    Nick Barker
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht and University Medical Centre Utrecht, Netherlands
    Cell Stem Cell 6:25-36. 2010
    ..The Lgr5 stem cell marker and culture method described here will be invaluable tools for accelerating research into gastric epithelial renewal, inflammation/infection, and cancer...
  11. pmc Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
    Toshiro Sato
    Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
    Nature 469:415-8. 2011
    ..In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell...
  12. doi request reprint Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas
    Arnout G Schepers
    Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen, and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands
    Science 337:730-5. 2012
    ..The Lgr5(+) cells are intermingled with Paneth cells near the adenoma base, a pattern reminiscent of the architecture of the normal crypt niche...
  13. doi request reprint Crypt stem cells as the cells-of-origin of intestinal cancer
    Nick Barker
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht and University Medical Centre Utrecht, Netherlands
    Nature 457:608-11. 2009
    ..Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia...
  14. doi request reprint Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex
    Vivian S W Li
    Hubrecht Institute, KNAW and University Medical Centre Utrecht, The Netherlands
    Cell 149:1245-56. 2012
    ..Subsequently, newly synthesized β-catenin can accumulate in a free cytosolic form and engage nuclear TCF transcription factors...
  15. pmc In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration
    Meritxell Huch
    Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Netherlands
    Nature 494:247-50. 2013
    ..These findings indicate that previous observations concerning Lgr5(+) stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous proliferation...
  16. doi request reprint Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
    Toshiro Sato
    Hubrecht Institute and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
    Nature 459:262-5. 2009
    ..We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche...
  17. ncbi request reprint Identification of stem cells in small intestine and colon by marker gene Lgr5
    Nick Barker
    Hubrecht Institute, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
    Nature 449:1003-7. 2007
    ..The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers...
  18. pmc T-cell factor 4 (Tcf7l2) maintains proliferative compartments in zebrafish intestine
    Vanesa Muncan
    Netherlands Institute for Developmental Biology, Center for Biomedical Research, Hubrecht Institute, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
    EMBO Rep 8:966-73. 2007
    ..This study underscores the involvement of Tcf4 in maintaining proliferative self-renewal in the intestine throughout life...
  19. ncbi request reprint Wnt activates the Tak1/Nemo-like kinase pathway
    Linda Smit
    Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    J Biol Chem 279:17232-40. 2004
    ..Thus, Wnt signal transduction through the canonical pathway activates beta-catenin/TCF, whereas Wnt signal transduction through the Tak1 pathway phosphorylates and inhibits TCF, which might function as a feedback mechanism...
  20. ncbi request reprint Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling
    Wim de Lau
    Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
    Nature 476:293-7. 2011
    ..These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues...
  21. ncbi request reprint EphB receptor activity suppresses colorectal cancer progression
    Eduard Batlle
    Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Nature 435:1126-30. 2005
    ..Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression...
  22. pmc The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis
    Tokameh Mahmoudi
    Hubrecht Institute and University Medical Centre Utrecht, Utrecht, The Netherlands
    PLoS Biol 8:e1000539. 2010
    ..The methyltransferase DOT1L may present an attractive candidate for drug targeting in colorectal cancer...
  23. doi request reprint Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin
    Hugo J Snippert
    Hubrecht Institute KNAW Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands
    Science 327:1385-9. 2010
    ..Adult Lgr6+ cells executed long-term wound repair, including the formation of new hair follicles. We conclude that Lgr6 marks the most primitive epidermal stem cell...
  24. ncbi request reprint Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
    Bon Kyoung Koo
    Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Nature 488:665-9. 2012
    ..We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation...
  25. ncbi request reprint Wnt signalling induces maturation of Paneth cells in intestinal crypts
    Johan H van Es
    Hubrecht Institute, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
    Nat Cell Biol 7:381-6. 2005
    ..These observations imply that Wnt signals in the crypt can separately drive a stem-cell/progenitor gene programme and a Paneth-cell maturation programme. In intestinal cancer, both gene programmes are activated simultaneously...
  26. pmc Peyer's patch M cells derived from Lgr5(+) stem cells require SpiB and are induced by RankL in cultured "miniguts"
    Wim de Lau
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, and University Medical Centre Utrecht, Utrecht, The Netherlands
    Mol Cell Biol 32:3639-47. 2012
    ..We conclude that RankL-induced expression of SpiB is essential for Lgr5 stem cell-derived epithelial precursors to develop into M cells...
  27. doi request reprint Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium
    Toshiro Sato
    Hubrecht Institute, KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands
    Gastroenterology 141:1762-72. 2011
    ..We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon...
  28. doi request reprint Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells
    Hugo J Snippert
    Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Cell 143:134-44. 2010
    ..Quantitative analysis shows that stem cell turnover follows a pattern of neutral drift dynamics...
  29. doi request reprint T-cell factor 4 (tcf7l2) is the main effector of Wnt signaling during zebrafish intestine organogenesis
    Ana Faro
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, The Netherlands
    Zebrafish 6:59-68. 2009
    ..This study reveals that Tcf4 (tcf7l2) is the major effector of Wnt signaling in the intestine during zebrafish organogenesis...
  30. doi request reprint Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine
    Hugo J Snippert
    Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    Gastroenterology 136:2187-2194.e1. 2009
    ..To determine whether there is a relationship between these markers, we investigated the intestinal expression pattern of Prom1/CD133 and created knock-in mice to visualize and trace Prom1(+) cells...
  31. ncbi request reprint Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells
    Johan H van Es
    Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
    Nature 435:959-63. 2005
    ..Our data indicate that gamma-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease...
  32. ncbi request reprint Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB
    Eduard Batlle
    Department of Immunology and Center for Biomedical Genetics, University Medical Center, Utrecht, The Netherlands
    Cell 111:251-63. 2002
    ..We conclude that in the intestinal epithelium beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin-B system...
  33. ncbi request reprint Many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the intestinal epithelium
    Michal Mokry
    Division of Pediatrics, Wilhelmina Children s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
    Gastroenterology 146:1040-7. 2014
    ..These studies have focused mainly on protein-coding genes. We investigated other functional elements in the human genome, such as regulatory regions...
  34. pmc Efficient double fragmentation ChIP-seq provides nucleotide resolution protein-DNA binding profiles
    Michal Mokry
    Cancer Genomics Center, Department of Medical Genetics, Hubrecht Institute and University Medical Center Utrecht, Utrecht, The Netherlands
    PLoS ONE 5:e15092. 2010
    ..Although optimized for the AB/SOLiD platform, the same approach may be applied to other platforms...
  35. ncbi request reprint The Intestinal Wnt/TCF Signature
    Laurens G van der Flier
    Hubrecht Institute, Netherlands Institute for Developmental Biology and Centre for Biomedical Genetics, Utrecht, The Netherlands
    Gastroenterology 132:628-32. 2007
    ..In colorectal cancer, activating mutations in the Wnt pathway transform epithelial cells through the inappropriate expression of a TCF4 target gene program, which is physiologically expressed in intestinal crypts...
  36. pmc The kinase TNIK is an essential activator of Wnt target genes
    Tokameh Mahmoudi
    Hubrecht Institute KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands
    EMBO J 28:3329-40. 2009
    ..siRNA depletion of TNIK followed by expression array analysis showed that TNIK is an essential, specific activator of Wnt transcriptional programme. This kinase may present an attractive candidate for drug targeting in colorectal cancer...
  37. pmc Hindgut defects and transformation of the gastro-intestinal tract in Tcf4(-/-)/Tcf1(-/-) embryos
    Alex Gregorieff
    Netherlands Institute for Developmental Biology and Center for Biomedical Genetics, Hubrecht Laboratory, Uppsalalaan, CT Utrecht, The Netherlands
    EMBO J 23:1825-33. 2004
    ..Our results reveal a novel role for Wnt signalling in early gut morphogenesis and suggest that specific Wnt-driven patterning events are determined by the unique tissue distribution of Tcf/Lef family members...
  38. doi request reprint MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway
    Ser Sue Ng
    Hubrecht Institute, KNAW and University Medical Centre Utrecht, Uppsalalaan 8, NL 3584 CT Utrecht, The Netherlands
    Biol Chem 391:171-80. 2010
    ..These results suggest that MAP3K1, previously reported as an Axin1 inter-actor in c-Jun NH(2)-terminal kinase pathway, is also involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes...
  39. ncbi request reprint The Wnt/beta-catenin pathway regulates cardiac valve formation
    Adam F L Hurlstone
    Netherlands Institute for Developmental Biology, Hubrecht Laboratory and Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
    Nature 425:633-7. 2003
    ..Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate...
  40. ncbi request reprint Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging
    Laila Ritsma
    1 Cancer Genomics Netherlands, Hubrecht Institute KNAW and University Medical Centre Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands 2
    Nature 507:362-5. 2014
    ..These findings establish a novel paradigm for stem-cell maintenance in which a dynamically heterogeneous cell population is able to function long term as a single stem-cell pool...
  41. doi request reprint Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl
    Daniele V F Tauriello
    Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
    Mol Cell 37:607-19. 2010
    ..Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses...
  42. doi request reprint Controlled gene expression in primary Lgr5 organoid cultures
    Bon Kyoung Koo
    Hubrecht Institute for Developmental Biology and Stem Cell Research, and University Medical Centre, Utrecht, The Netherlands
    Nat Methods 9:81-3. 2012
    ..We present here a method based on Cre recombinase-inducible retrovirus vectors that allows the conditional manipulation of gene expression in primary mouse organoid culture systems...
  43. doi request reprint Intestinal regeneration: YAP-tumor suppressor and oncoprotein?
    Vivian S W Li
    Hubrecht Institute KNAW and University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
    Curr Biol 23:R110-2. 2013
    ..A recent study paradoxically reports that genetic removal of YAP enhances intestinal stem cell expansion and regeneration...
  44. doi request reprint Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex
    Jean Paul ten Klooster
    Hubrecht Institute, KNAW and University Medical Centre, Utrecht, The Netherlands
    Dev Cell 16:551-62. 2009
    ..These data define a brush border induction pathway downstream of the Lkb1/Strad/Mo25 polarization complex, yet separate from other polarity events...
  45. pmc Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells
    Pantelis Hatzis
    Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Mol Cell Biol 28:2732-44. 2008
    ..The TCF4-binding regions significantly correlate with Wnt-responsive gene expression profiles derived from primary human adenomas and often behave as beta-catenin/TCF4-dependent enhancers in transient reporter assays...
  46. ncbi request reprint Wnt signaling in the intestinal epithelium: from endoderm to cancer
    Alex Gregorieff
    Netherlands Institute for Developmental Biology, Hubrecht Laboratory, 3584 CT Utrecht, The Netherlands
    Genes Dev 19:877-90. 2005
    ..In this review, we outline current understanding of the physiological role of Wnt signaling in intestinal biology. From this perspective, we then describe how mutational subversion of the Wnt cascade leads to colorectal cancer...
  47. pmc Wnt signaling, lgr5, and stem cells in the intestine and skin
    Andrea Haegebarth
    Hubrecht Institute and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The
    Am J Pathol 174:715-21. 2009
    ..This review attempts to provide a comprehensive overview of the stem cell compartments in the intestine and skin with a focus on the cycling, yet long-lived and multipotent, Lgr5(+ve) stem cell populations...
  48. ncbi request reprint Thymocyte development: drama without Brahma
    Hans Clevers
    Hubrecht Laboratory, Center for Biomedical Genetics, Utrecht, The Netherlands
    Immunity 19:157-8. 2003
  49. ncbi request reprint Wnt breakers in colon cancer
    Hans Clevers
    Hubrecht Laboratory, 3584 CT Utrecht, The Netherlands
    Cancer Cell 5:5-6. 2004
    ..Ultimately, such inhibitors could become a novel class of smart anticancer drugs...
  50. ncbi request reprint De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine
    Anna Pavlina G Haramis
    Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, Netherlands
    Science 303:1684-6. 2004
    ..Many JP cases are known to harbor mutations in BMP pathway genes. These data indicate that intestinal BMP signaling represses de novo crypt formation and polyp growth...
  51. pmc Integrated genome-wide analysis of transcription factor occupancy, RNA polymerase II binding and steady-state RNA levels identify differentially regulated functional gene classes
    Michal Mokry
    Hubrecht Institute KNAW and University Medical Center, 3584 CT Utrecht, The Netherlands
    Nucleic Acids Res 40:148-58. 2012
    ..These categories are strongly enriched for genes from different functional classes. Our results demonstrate a complementary value in Pol II chip-seq and RNA-seq approaches for better understanding of gene expression regulation...
  52. doi request reprint Lgr5(+ve) stem/progenitor cells contribute to nephron formation during kidney development
    Nick Barker
    Hubrecht Institute for Developmental Biology and Stem Cell Research University Medical Centre Utrecht, Utrecht, The Netherlands
    Cell Rep 2:540-52. 2012
    ....
  53. pmc Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors
    Johan H van Es
    Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, Utrecht 3584CT, Netherlands
    Nat Commun 1:18. 2010
    ..In this paper, we demonstrate that the conversion of intestinal stem cells into goblet cells upon inhibition of the Notch signalling pathway requires Math1...
  54. doi request reprint Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells
    Nick Barker
    Hubrecht Institute, Uppsalalaan, Utrecht, The Netherlands
    Gastroenterology 138:1681-96. 2010
    ..Further studies of these markers might reveal adult stem cell populations in additional tissues. Identification of the ligands for Lgr5 and 6 will help elucidate stem cell functions and modes of intracellular signaling...
  55. doi request reprint Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand
    Sylvia F Boj
    Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands
    Cell 151:1595-607. 2012
    ..Furthermore, liver-specific TCF4 overexpression increases hepatic glucose production. These observations imply that TCF4 directly activates metabolic genes and that inhibition of Wnt signaling may be beneficial in metabolic disease...
  56. ncbi request reprint Stem cells, self-renewal, and differentiation in the intestinal epithelium
    Laurens G van der Flier
    Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands
    Annu Rev Physiol 71:241-60. 2009
    ..These studies describe a genetic hierarchy responsible for cell fate commitment in normal gut physiology. Where relevant we also mention aberrant deregulation of these molecular pathways that results in colon cancer...
  57. pmc Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector
    Marc van de Wetering
    Hubrecht Laboratory, Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    EMBO Rep 4:609-15. 2003
    ..The inhibition of two other genes using this vector system shows that it should be useful for the inducible knockdown of gene expression...
  58. pmc Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc
    Vanesa Muncan
    Hubrecht Laboratory, Nederlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Mol Cell Biol 26:8418-26. 2006
    ..c-Myc appears essential for crypt progenitor cells to provide the necessary biosynthetic capacity to successfully progress through the cell cycle...
  59. doi request reprint Differentiated human colorectal cancer cells protect tumor-initiating cells from irinotecan
    Benjamin L Emmink
    Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
    Gastroenterology 141:269-78. 2011
    ..We studied the relationship between resistance to the topoisomerase I inhibitor irinotecan and tumor-initiating potential in human colonosphere cultures and in mice with colorectal xenograft tumors...
  60. ncbi request reprint The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells
    Marc van de Wetering
    Department of Immunology and Center for Biomedical Genetics, University Medical Center, 3584 CX, Utrecht, The Netherlands
    Cell 111:241-50. 2002
    ..Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells...
  61. doi request reprint Wnt-induced transcriptional activation is exclusively mediated by TCF/LEF
    Jurian Schuijers
    Hubrecht Institute KNAW, University Medical Centre Utrecht, Utrecht, The Netherlands
    EMBO J 33:146-56. 2014
    ..Our results indicate that β-catenin is tethered to chromatin overwhelmingly through the TCF/LEF transcription factors in these three systems. ..
  62. pmc Active Wnt signaling in response to cardiac injury
    Martinus I F J Oerlemans
    Department of Cardiology, University Medical Centre Utrecht, The Netherlands
    Basic Res Cardiol 105:631-41. 2010
    ..Given its broad role during the healing phase after cardiac injury, additional research seems warranted before a therapeutic approach on Wnt to enhance cardiac regeneration can be carried out safely...
  63. ncbi request reprint Wnt, stem cells and cancer in the intestine
    Daniel Pinto
    Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands
    Biol Cell 97:185-96. 2005
    ....
  64. ncbi request reprint Live and let die in the intestinal epithelium
    Elena Sancho
    Centre for Biomedical Genetics, Hubrecht Laboratorium, Koninklijke Nederlandse Akademie van Wetenschappen, Utrecht, The Netherlands
    Curr Opin Cell Biol 15:763-70. 2003
    ..Wnt signalling appears to control most of these events...
  65. pmc Canonical Wnt signals are essential for homeostasis of the intestinal epithelium
    Daniel Pinto
    Netherlands Institute for Developmental Biology, Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Genes Dev 17:1709-13. 2003
    ..Thus, our data are the first to establish a direct requirement for Wnt ligands in driving proliferation in the intestinal epithelium, and also define an unexpected role for Wnts in controlling secretory cell differentiation...
  66. ncbi request reprint Caught up in a Wnt storm: Wnt signaling in cancer
    Rachel H Giles
    Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
    Biochim Biophys Acta 1653:1-24. 2003
    ....
  67. doi request reprint Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells
    Henner F Farin
    Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Utrecht, The Netherlands
    Gastroenterology 143:1518-1529.e7. 2012
    ..Paneth cells support stem cells by secreting Wnt, but little is known about the exact sources and primary functions of individual Wnt family members...
  68. ncbi request reprint AU-rich elements and alternative splicing in the beta-catenin 3'UTR can influence the human beta-catenin mRNA stability
    Andrea Thiele
    Hubrecht Laboratory, The Netherlands Institute of Developmental Biology, Uppsalalaan 8, NL 3584 CT Utrecht, The Netherlands
    Exp Cell Res 312:2367-78. 2006
    ..These results suggest that alternative splicing and AREs can act together in regulating beta-catenin mRNA stability and thereby provide a step of controlling the cellular beta-catenin concentration...
  69. doi request reprint Rap2A links intestinal cell polarity to brush border formation
    Martijn Gloerich
    Molecular Cancer Research, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands
    Nat Cell Biol 14:793-801. 2012
    ..Thus, epithelial cell polarization is translated directly into the acquisition of brush borders through a small G protein signalling module whose action is positioned by a cortical lipid cue...
  70. ncbi request reprint WNT signaling in the normal intestine and colorectal cancer
    Wim de Lau
    Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands
    Front Biosci 12:471-91. 2007
    ..The Eph/Ephrin system also operates to limit progression of colorectal cancer beyond the early stages...
  71. doi request reprint Fishing for intestinal cancer models: unraveling gastrointestinal homeostasis and tumorigenesis in zebrafish
    Ana Faro
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, The Netherlands
    Zebrafish 6:361-76. 2009
    ..An appealing avenue for cancer research in zebrafish is large-scale screens to identify chemotherapeutic and chemopreventive agents in conjunction with the in vivo imaging approaches that zebrafish affords...
  72. ncbi request reprint Signaling mucins in the (S)limelight
    Hans Clevers
    Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, Utrecht 3584 CT, The Netherlands
    Dev Cell 7:150-1. 2004
    ..In a recent issue of Genes & Development, Cullen et al. show that the C terminus of membrane mucin-like Msb2 activates a CDC42/MAPK cascade to control filamentous growth of baker's yeast...
  73. ncbi request reprint Transcription factor target practice
    Frank C P Holstege
    Department of Physiological Chemistry, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
    Cell 124:21-3. 2006
    ..Although still under development, these studies provide an efficient way to decipher regulatory networks...
  74. ncbi request reprint Inflating cell numbers by Wnt
    Hans Clevers
    Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands
    Mol Cell 10:1260-1. 2002
    ..As a downstream target gene of the Wnt cascade, the bicoid-related transcription factor Pitx2 directly drives proliferation in these tissues...
  75. pmc Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins
    Jurian Schuijers
    Hubrecht Institute KNAW, University Medical Centre Utrecht, The Netherlands
    EMBO J 31:2685-96. 2012
    ..The story has come full circle with the finding that the stem cell marker Lgr5 constitutes the receptor for R-spondins and occurs in complex with Frizzled/Lrp...
  76. ncbi request reprint Wnt signaling: Ig-norrin the dogma
    Hans Clevers
    Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
    Curr Biol 14:R436-7. 2004
    ..Unexpectedly, a non-Wnt ligand for this receptor complex has now been discovered. This novel ligand, Norrin, is mutated in the hereditary ocular Norrie syndrome...
  77. pmc Wnt signaling, stem cells, and cancer of the gastrointestinal tract
    Arnout Schepers
    Hubrecht Institute, KNAW and University Medical Centre Utrecht, 3584CT Utrecht, The Netherlands
    Cold Spring Harb Perspect Biol 4:a007989. 2012
    ..Recent studies indicate that Wnt signaling plays a central role in the biology of gastrointestinal stem cells. Furthermore, mutational activation of the Wnt cascade is the principle cause of colon cancer...
  78. pmc The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers
    Javier Munoz
    Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, University, The Netherlands
    EMBO J 31:3079-91. 2012
    ..Using this resource, we find-and confirm by independent approaches-that the proposed quiescent/'+4' stem cell markers Bmi1, Tert, Hopx and Lrig1 are robustly expressed in CBC cells...
  79. ncbi request reprint Tracking down the stem cells of the intestine: strategies to identify adult stem cells
    Nick Barker
    Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, The Netherlands
    Gastroenterology 133:1755-60. 2007
  80. doi request reprint In situ hybridization to identify gut stem cells
    Alex Gregorieff
    Hubrecht Institute, Utrecht, The Netherlands
    Curr Protoc Stem Cell Biol . 2010
    ..This methodology allows researchers to quickly visualize the expression profile of putative stem cell markers with a high degree of sensitivity and resolution...