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Plasticity of the brush border — the yin and yang of intestinal homeostasis

Nature Reviews Gastroenterology & Hepatology volume 13, pages 161–174 (2016)Cite this article

Subjects

Key Points

  • The brush border is a complex and highly plastic organelle required for intestinal homeostasis and is specialized for absorption of nutrients

  • Thousands of tightly packed microvilli form the brush border together with the area they are located on, the so-called terminal web

  • The brush border constitutes a biochemical and mechanical interface between the intestinal lumen and the internal milieu

  • Inherited or acquired genetic brush border defects lead to intestinal insufficiency and diarrhoea

  • Pathogens and inflammatory processes can alter the integrity of the brush border, either by actively remodelling or damaging its structure

Abstract

The brush border on the apical surface of enterocytes is a highly specialized structure well-adapted for efficient digestion and nutrient transport, whilst at the same time providing a protective barrier for the intestinal mucosa. The brush border is constituted of a densely ordered array of microvilli, protrusions of the plasma membrane, which are supported by actin-based microfilaments and interacting proteins and anchored in an apical network of actomyosin and intermediate filaments, the so-called terminal web. The highly dynamic, specialized apical domain is both an essential partner for the gut microbiota and an efficient signalling platform that enables adaptation to physiological stimuli from the external and internal milieu. Nevertheless, genetic alterations or various pathological stresses, such as infection, inflammation, and mechanical or nutritional alterations, can jeopardize this equilibrium and compromise intestinal functions. Long-time neglected, the intestinal brush-border shall be enlightening again as the central actor of the complex but essential intestinal homeostasis. Here, we review the processes and components involved in brush border organization and discuss pathological mechanisms that can induce brush border defects and their physiological consequences.

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Figure 1: Structure and composition of the brush border.
Figure 2: Brush border malformations in human pathogenic or pathological conditions.

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References

  1. Revenu, C., Athman, R., Robine, S. & Louvard, D. The co-workers of actin filaments: from cell structures to signals. Nat. Rev. Mol. Cell Biol. 5, 635–646 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Crawley, S. W., Mooseker, M. S. & Tyska, M. J. Shaping the intestinal brush border. J. Cell Biol. 207, 441–451 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tilney, L. G., Tilney, M. S. & DeRosier, D. J. Actin filaments, stereocilia, and hair cells: how cells count and measure. Annu. Rev. Cell Biol. 8, 257–274 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. Maroux, S., Coudrier, E., Feracci, H., Gorvel, J. P. & Louvard, D. Molecular organization of the intestinal brush border. Biochimie 70, 1297–1306 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Louvard, D., Kedinger, M. & Hauri, H. P. The differentiating intestinal epithelial cell: establishment and maintenance of functions through interactions between cellular structures. Annu. Rev. Cell Biol. 8, 157–195 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Shifrin, D. A. Jr & Tyska, M. J. Ready...aim...fire into the lumen: a new role for enterocyte microvilli in gut host defense. Gut Microbes 3, 460–462 (2012).

    Article  PubMed  Google Scholar 

  7. Pollard, T. D. & Mooseker, M. S. Direct measurement of actin polymerization rate constants by electron microscopy of actin filaments nucleated by isolated microvillus cores. J. Cell Biol. 88, 654–659 (1981).

    Article  CAS  PubMed  Google Scholar 

  8. Mooseker, M. S. & Tilney, L. G. Organization of an actin filament-membrane complex. Filament polarity and membrane attachment in the microvilli of intestinal epithelial cells. J. Cell Biol. 67, 725–743 (1975).

    Article  CAS  PubMed  Google Scholar 

  9. Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Edwards, M. et al. Capping protein regulators fine-tune actin assembly dynamics. Nat. Rev. Mol. Cell Biol. 15, 677–689 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bartles, J. R. Parallel actin bundles and their multiple actin-bundling proteins. Curr. Opin. Cell Biol. 12, 72–78 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fehon, R. G., McClatchey, A. I. & Bretscher, A. Organizing the cell cortex: the role of ERM proteins. Nat. Rev. Mol. Cell Biol. 11, 276–287 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cooper, J. A. & Pollard, T. D. Effect of capping protein on the kinetics of actin polymerization. Biochemistry 24, 793–799 (1985).

    Article  CAS  PubMed  Google Scholar 

  14. Caldwell, J. E., Heiss, S. G., Mermall, V. & Cooper, J. A. Effects of CapZ, an actin capping protein of muscle, on the polymerization of actin. Biochemistry 28, 8506–8514 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Schafer, D. A., Mooseker, M. S. & Cooper, J. A. Localization of capping protein in chicken epithelial cells by immunofluorescence and biochemical fractionation. J. Cell Biol. 118, 335–346 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Coluccio, L. M. & Bretscher, A. Reassociation of microvillar core proteins: making a microvillar core in vitro. J. Cell Biol. 108, 495–502 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Glenney, J. R. Jr, Bretscher, A. & Weber, K. Calcium control of the intestinal microvillus cytoskeleton: its implications for the regulation of microfilament organizations. Proc. Natl Acad. Sci. USA 77, 6458–6462 (1980).

    Article  CAS  PubMed  Google Scholar 

  18. Bretscher, A. & Weber, K. Fimbrin, a new microfilament-associated protein present in microvilli and other cell surface structures. J. Cell Biol. 86, 335–340 (1980).

    Article  CAS  PubMed  Google Scholar 

  19. Bretscher, A. & Weber, K. Villin: the major microfilament-associated protein of the intestinal microvillus. Proc. Natl Acad. Sci. USA 76, 2321–2325 (1979).

    Article  CAS  PubMed  Google Scholar 

  20. Bretscher, A. & Weber, K. Villin is a major protein of the microvillus cytoskeleton which binds both G and F actin in a calcium-dependent manner. Cell 20, 839–847 (1980).

    Article  CAS  PubMed  Google Scholar 

  21. Robine, S. et al. Can villin be used to identify malignant and undifferentiated normal digestive epithelial cells? Proc. Natl Acad. Sci. USA 82, 8488–8492 (1985).

    Article  CAS  PubMed  Google Scholar 

  22. Costa de Beauregard, M. A., Pringault, E., Robine, S. & Louvard, D. Suppression of villin expression by antisense RNA impairs brush border assembly in polarized epithelial intestinal cells. EMBO J. 14, 409–421 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pinson, K. I., Dunbar, L., Samuelson, L. & Gumucio, D. L. Targeted disruption of the mouse villin gene does not impair the morphogenesis of microvilli. Dev. Dyn. 211, 109–121 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. George, S. P., Wang, Y., Mathew, S. Srinivasan, K. & Khurana, S. Dimerization and actin-bundling properties of villin and its role in the assembly of epithelial cell brush borders. J. Biol. Chem. 282, 26528–26541 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Friederich, E., Vancompernolle, K., Louvard, D. & Vandekerckhove, J. Villin function in the organization of the actin cytoskeleton. Correlation of in vivo effects to its biochemical activities in vitro. J. Biol. Chem. 274, 26751–26760 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Khurana, S. & George, S. P. Regulation of cell structure and function by actin-binding proteins: villin's perspective. FEBS Lett. 582, 2128–2139 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kumar, N., Tomar, A., Parrill, A. L. & Khurana, S. Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J. Biol. Chem. 279, 45036–45046 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Glenney, J. R. Jr, Geisler, N., Kaulfus, P. & Weber, K. Demonstration of at least two different actin-binding sites in villin, a calcium-regulated modulator of F-actin organization. J. Biol. Chem. 256, 8156–8161 (1981).

    CAS  PubMed  Google Scholar 

  29. Ferrary, E. et al. In vivo, villin is required for Ca2+-dependent F-actin disruption in intestinal brush borders. J. Cell Biol. 146, 819–830 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kumar, N. & Khurana, S. Identification of a functional switch for actin severing by cytoskeletal proteins. J. Biol. Chem. 279, 24915–24918 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Kumar, N., Zhao, P., Tomar, A., Galea, C. A. & Khurana, S. Association of villin with phosphatidylinositol 4,5-bisphosphate regulates the actin cytoskeleton. J. Biol. Chem. 279, 3096–3110 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Lin, C. S., Shen, W., Chen, Z. P., Tu, Y. H. & Matsudaira, P. Identification of I-plastin, a human fimbrin isoform expressed in intestine and kidney. Mol. Cell. Biol. 14, 2457–2467 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Grimm-Gunter, E. M. et al. Plastin 1 binds to keratin and is required for terminal web assembly in the intestinal epithelium. Mol. Biol. Cell 20, 2549–2562 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bartles, J. R., Zheng, L., Li, A., Wierda, A. & Chen, B. Small espin: a third actin-bundling protein and potential forked protein ortholog in brush border microvilli. J. Cell Biol. 143, 107–119 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Disanza, A. et al. Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8–IRSp53 complex. Nat. Cell Biol. 8, 1337–1347 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Hertzog, M. et al. Molecular basis for the dual function of Eps8 on actin dynamics: bundling and capping. PLoS Biol. 8, e1000387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Croce, A. et al. A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans. Nat. Cell Biol. 6, 1173–1179 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Berryman, M., Franck, Z. & Bretscher, A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J. Cell Sci. 105, 1025–1043 (1993).

    CAS  PubMed  Google Scholar 

  39. Tyska, M. J. et al. Myosin-1a is critical for normal brush border structure and composition. Mol. Biol. Cell 16, 2443–2457 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Saotome, I., Curto, M. & McClatchey, A. I. Ezrin is essential for epithelial organization and villus morphogenesis in the developing intestine. Dev. Cell 6, 855–864 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Fievet, B. T. et al. Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J. Cell Biol. 164, 653–659 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bretscher, A., Reczek, D. & Berryman, M. Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures. J. Cell Sci. 110, 3011–3018 (1997).

    CAS  PubMed  Google Scholar 

  43. ten Klooster, J. P. et al. Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex. Dev. Cell 16, 551–562 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Shiue, H., Musch, M. W., Wang, Y., Chang, E. B. & Turner, J. R. Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation. J. Biol. Chem. 280, 1688–1695 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Wald, F. A. et al. Atypical protein kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells. J. Cell Sci. 121, 644–654 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Viswanatha, R., Ohouo, P. Y., Smolka, M. B. & Bretscher, A. Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells. J. Cell Biol. 199, 969–984 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dhekne, H. S. et al. Myosin Vb and Rab11a regulate phosphorylation of ezrin in enterocytes. J. Cell Sci. 127, 1007–1017 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Reczek, D., Berryman, M. & Bretscher, A. Identification of EBP50: a PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family. J. Cell Biol. 139, 169–179 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Morales, F. C., Takahashi, Y., Kreimann, E. L. & Georgescu, M. M. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc. Natl Acad. Sci. USA 101, 17705–17710 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Garbett, D., LaLonde, D. P. & Bretscher, A. The scaffolding protein EBP50 regulates microvillar assembly in a phosphorylation-dependent manner. J. Cell Biol. 191, 397–413 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chiba, H. et al. The nuclear receptor hepatocyte nuclear factor 4α acts as a morphogen to induce the formation of microvilli. J. Cell Biol. 175, 971–980 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. LaLonde, D. P., Garbett, D. & Bretscher, A. A regulated complex of the scaffolding proteins PDZK1 and EBP50 with ezrin contribute to microvillar organization. Mol. Biol. Cell 21, 1519–1529 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Casaletto, J. B., Saotome, I., Curto, M. & McClatchey, A. I. Ezrin-mediated apical integrity is required for intestinal homeostasis. Proc. Natl Acad. Sci. USA 108, 11924–11929 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Gobel, V., Barrett, P. L., Hall, D. H. & Fleming, J. T. Lumen morphogenesis in C. elegans requires the membrane-cytoskeleton linker erm-1. Dev. Cell 6, 865–873 (2004).

    Article  PubMed  Google Scholar 

  55. Van Furden, D., Johnson, K., Segbert, C. & Bossinger, O. The C. elegans ezrin-radixin-moesin protein ERM-1 is necessary for apical junction remodelling and tubulogenesis in the intestine. Dev. Biol. 272, 262–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Khan, L. A. et al. Intracellular lumen extension requires ERM-1-dependent apical membrane expansion and AQP-8-mediated flux. Nat. Cell Biol. 15, 143–156 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Baas, A. F. et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Rodriguez-Boulan, E. & Macara, I. G. Organization and execution of the epithelial polarity programme. Nat. Rev. Mol. Cell Biol. 15, 225–242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mooseker, M. S. & Cheney, R. E. Unconventional myosins. Annu. Rev. Cell Dev. Biol. 11, 633–675 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Tyska, M. J. & Mooseker, M. S. MYO1A (brush border myosin I) dynamics in the brush border of LLC-PK1-CL4 cells. Biophys. J. 82, 1869–1883 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tyska, M. J. & Mooseker, M. S. A role for myosin-1A in the localization of a brush border disaccharidase. J. Cell Biol. 165, 395–405 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Loomis, P. A. et al. Espin cross-links cause the elongation of microvillus-type parallel actin bundles in vivo. J. Cell Biol. 163, 1045–1055 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zheng, L. et al. The deaf jerker mouse has a mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and lacks espins. Cell 102, 377–385 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Revenu, C. et al. A new role for the architecture of microvillar actin bundles in apical retention of membrane proteins. Mol. Biol. Cell 23, 324–336 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zwaenepoel, I. et al. Ezrin regulates microvillus morphogenesis by promoting distinct activities of Eps8 proteins. Mol. Biol. Cell 23, 1080–1094 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Crawley, S. W. et al. Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion. Cell 157, 433–446 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Atuma, C., Strugala, V., Allen, A. & Holm, L. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G922–G929 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. McGuckin, M. A., Linden, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265–278 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Fath, K. R., Mamajiwalla, S. N. & Burgess, D. R. The cytoskeleton in development of epithelial cell polarity. J. Cell Sci. Suppl. 17, 65–73 (1993).

    Article  CAS  PubMed  Google Scholar 

  70. Hirokawa, N., Tilney, L. G., Fujiwara, K. & Heuser, J. E. Organization of actin, myosin, and intermediate filaments in the brush border of intestinal epithelial cells. J. Cell Biol. 94, 425–443 (1982).

    Article  CAS  PubMed  Google Scholar 

  71. Moll, R. et al. The human gene encoding cytokeratin 20 and its expression during fetal development and in gastrointestinal carcinomas. Differentiation 53, 75–93 (1993).

    Article  CAS  PubMed  Google Scholar 

  72. Salas, P. J. Insoluble γ-tubulin-containing structures are anchored to the apical network of intermediate filaments in polarized CACO-2 epithelial cells. J. Cell Biol. 146, 645–658 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Salas, P. J., Rodriguez, M. L., Viciana, A. L., Vega-Salas, D. E. & Hauri, H. P. The apical submembrane cytoskeleton participates in the organization of the apical pole in epithelial cells. J. Cell Biol. 137, 359–375 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ameen, N. A., Figueroa, Y. & Salas, P. J. Anomalous apical plasma membrane phenotype in CK8-deficient mice indicates a novel role for intermediate filaments in the polarization of simple epithelia. J. Cell Sci. 114, 563–575 (2001).

    CAS  PubMed  Google Scholar 

  75. Owens, D. W. et al. Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients. J. Cell Sci. 117, 1989–1999 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Peterson, M. D., Bement, W. M. & Mooseker, M. S. An in vitro model for the analysis of intestinal brush border assembly. II. Changes in expression and localization of brush border proteins during cell contact-induced brush border assembly in Caco-2BBe cells. J. Cell Sci. 105, 461–472 (1993).

    CAS  PubMed  Google Scholar 

  77. Heintzelman, M. B., Hasson, T. & Mooseker, M. S. Multiple unconventional myosin domains of the intestinal brush border cytoskeleton. J. Cell Sci. 107, 3535–3543 (1994).

    CAS  PubMed  Google Scholar 

  78. Bazellieres, E. et al. Apico-basal elongation requires a drebrin-E–EB3 complex in columnar human epithelial cells. J. Cell Sci. 125, 919–931 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Lecuit, T. & Yap, A. S. E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat. Cell Biol. 17, 533–539 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Mooseker, M. S. Brush border motility. Microvillar contraction in triton-treated brush borders isolated from intestinal epithelium. J. Cell Biol. 71, 417–433 (1976).

    Article  CAS  PubMed  Google Scholar 

  81. Keller, T. C. 3rd & Mooseker, M. S. Ca++-calmodulin-dependent phosphorylation of myosin, and its role in brush border contraction in vitro. J. Cell Biol. 95, 943–959 (1982).

    Article  CAS  PubMed  Google Scholar 

  82. Keller, T. C. 3rd, Conzelman, K. A., Chasan, R. & Mooseker, M. S. Role of myosin in terminal web contraction in isolated intestinal epithelial brush borders. J. Cell Biol. 100, 1647–1655 (1985).

    Article  CAS  PubMed  Google Scholar 

  83. Klingner, C. et al. Isotropic actomyosin dynamics promote organization of the apical cell cortex in epithelial cells. J. Cell Biol. 207, 107–121 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Makarova, O., Roh, M. H., Liu, C. J., Laurinec, S. & Margolis, B. Mammalian Crumbs3 is a small transmembrane protein linked to protein associated with Lin-7 (Pals1). Gene 302, 21–29 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Roh, M. H., Fan, S., Liu, C. J. & Margolis, B. The Crumbs3–Pals1 complex participates in the establishment of polarity in mammalian epithelial cells. J. Cell Sci. 116, 2895–2906 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Lemmers, C. et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol. Biol. Cell 15, 1324–1333 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Whiteman, E. L. et al. Crumbs3 is essential for proper epithelial development and viability. Mol. Cell. Biol. 34, 43–56 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Reifen, R. M., Cutz, E., Griffiths, A. M., Ngan, B. Y. & Sherman, P. M. Tufting enteropathy: a newly recognized clinicopathological entity associated with refractory diarrhea in infants. J. Pediatr. Gastroenterol. Nutr. 18, 379–385 (1994).

    Article  CAS  PubMed  Google Scholar 

  89. Goulet, O. et al. Intractable diarrhea of infancy with epithelial and basement membrane abnormalities. J. Pediatr. 127, 212–219 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Salomon, J. et al. Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form. Hum. Genet. 133, 299–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Maghzal, N., Kayali, H. A., Rohani, N., Kajava, A. V. & Fagotto, F. EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC. Dev. Cell 27, 263–277 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Vacca, B. et al. Drebrin E depletion in human intestinal epithelial cells mimics Rab8a loss of function. Hum. Mol. Genet. 23, 2834–2846 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Goulet, O., Salomon, J., Ruemmele, F., de Serres, N. P. & Brousse, N. Intestinal epithelial dysplasia (tufting enteropathy). Orphanet J. Rare Dis. 2, 20 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kawaguchi, T. et al. Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor. J. Biol. Chem. 272, 27558–27564 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Marlor, C. W. et al. Identification and cloning of human placental bikunin, a novel serine protease inhibitor containing two Kunitz domains. J. Biol. Chem. 272, 12202–12208 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Patey, N. et al. Distribution of cell adhesion molecules in infants with intestinal epithelial dysplasia (tufting enteropathy). Gastroenterology 113, 833–843 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Slae, M. A. et al. Syndromic congenital diarrhea because of the SPINT2 mutation showing enterocyte tufting and unique electron microscopy findings. Clin. Dysmorphol. 22, 118–120 (2013).

    Article  PubMed  Google Scholar 

  98. Davidson, G. P., Cutz, E., Hamilton, J. R. & Gall, D. G. Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy. Gastroenterology 75, 783–790 (1978).

    Article  CAS  PubMed  Google Scholar 

  99. Cutz, E. et al. Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation. N. Engl. J. Med. 320, 646–651 (1989).

    Article  CAS  PubMed  Google Scholar 

  100. Ameen, N. A. & Salas, P. J. Microvillus inclusion disease: a genetic defect affecting apical membrane protein traffic in intestinal epithelium. Traffic 1, 76–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Ruemmele, F. M., Schmitz, J. & Goulet, O. Microvillous inclusion disease (microvillous atrophy). Orphanet J. Rare Dis. 1, 22 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Sato, T. et al. The Rab8 GTPase regulates apical protein localization in intestinal cells. Nature 448, 366–369 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Muller, T. et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat. Genet. 40, 1163–1165 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. van der Velde, K. J. et al. An overview and online registry of microvillus inclusion disease patients and their MYO5B mutations. Hum. Mutat. 34, 1597–1605 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Roland, J. T. et al. Rab GTPase–Myo5B complexes control membrane recycling and epithelial polarization. Proc. Natl Acad. Sci. USA 108, 2789–2794 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Sobajima, T. et al. Rab11a is required for apical protein localisation in the intestine. Biol. Open 4, 86–94 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Knowles, B. C. et al. Rab11a regulates syntaxin 3 localization and microvillus assembly in enterocytes. J. Cell Sci. 128, 1617–1626 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Melendez, J. et al. Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice. Gastroenterology 145, 808–819 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Knowles, B. C. et al. Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease. J. Clin. Invest. 124, 2947–2962 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Erickson, R. P., Larson-Thome, K., Valenzuela, R. K., Whitaker, S. E. & Shub, M. D. Navajo microvillous inclusion disease is due to a mutation in MYO5B. Am. J. Med. Genet. A 146A, 3117–3119 (2008).

  111. Raafat, F., Green, N. J., Nathavitharana, K. A. & Booth, I. W. Intestinal microvillous dystrophy: a variant of microvillous inclusion disease or a new entity? Hum. Pathol. 25, 1243–1248 (1994).

    Article  CAS  PubMed  Google Scholar 

  112. Mierau, G. W., Wills, E. J., Wyatt-Ashmead, J., Hoffenberg, E. J. & Cutz, E. Microvillous inclusion disease: report of a case with atypical features. Ultrastruct. Pathol. 25, 517–521 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Weeks, D. A., Zuppan, C. W., Malott, R. L. & Mierau, G. W. Microvillous inclusion disease with abundant vermiform, electron-lucent vesicles. Ultrastruct. Pathol. 27, 337–340 (2003).

    Article  PubMed  Google Scholar 

  114. Wiegerinck, C. L. et al. Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology 147, 65–68.e10 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Janecke, A. R. et al. Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum. Mol. Genet. 24, 6614–6623 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Muller, T. et al. Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. Gut http://dx.doi.org/10.1136/gutjnl-2015-309441 (2015).

  117. Sullivan, S. et al. Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea. Inflamm. Bowel Dis. 15, 261–274 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Chen, T. et al. Myosin VI mediates the movement of NHE3 down the microvillus in intestinal epithelial cells. J. Cell Sci. 127, 3535–3545 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ubelmann, F. et al. Enterocyte loss of polarity and gut wound healing rely upon the F-actin-severing function of villin. Proc. Natl Acad. Sci. USA 110, E1380–E1389 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Thiery, J. P. & Sleeman, J. P. Complex networks orchestrate epithelial–mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7, 131–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Chanrion, M. et al. Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. Nat. Commun. 5, 5005 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lichtenberger, L. M. The hydrophobic barrier properties of gastrointestinal mucus. Annu. Rev. Physiol. 57, 565–583 (1995).

    Article  CAS  PubMed  Google Scholar 

  123. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Pelaseyed, T. et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8–20 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Klaasen, H. L. et al. Intestinal, segmented, filamentous bacteria in a wide range of vertebrate species. Lab. Anim. 27, 141–150 (1993).

    Article  CAS  PubMed  Google Scholar 

  126. Yin, Y. et al. Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens. ISME J. 7, 615–621 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Chen, C. C., Baylor, M. & Bass, D. M. Murine intestinal mucins inhibit rotavirus infection. Gastroenterology 105, 84–92 (1993).

    Article  CAS  PubMed  Google Scholar 

  130. Wikman, A., Karlsson, J., Carlstedt, I. & Artursson, P. A drug absorption model based on the mucus layer producing human intestinal goblet cell line HT29-H. Pharm. Res. 10, 843–852 (1993).

    Article  CAS  PubMed  Google Scholar 

  131. Iiboshi, Y. et al. Adhesive mucous gel layer and mucus release as intestinal barrier in rats. JPEN J. Parenter. Enteral Nutr. 20, 98–104 (1996).

    Article  CAS  PubMed  Google Scholar 

  132. McAuley, J. L. et al. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J. Clin. Invest. 117, 2313–2324 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bates, J. M., Akerlund, J., Mittge, E. & Guillemin, K. Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell Host Microbe 2, 371–382 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Goldberg, R. F. et al. Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition. Proc. Natl Acad. Sci. USA 105, 3551–3556 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Shifrin, D. A. Jr et al. Enterocyte microvillus-derived vesicles detoxify bacterial products and regulate epithelial–microbial interactions. Curr. Biol. 22, 627–631 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. McConnell, R. E. et al. The enterocyte microvillus is a vesicle-generating organelle. J. Cell Biol. 185, 1285–1298 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Finlay, B. B. & Falkow, S. Salmonella interactions with polarized human intestinal Caco-2 epithelial cells. J. Infect. Dis. 162, 1096–1106 (1990).

    Article  CAS  PubMed  Google Scholar 

  138. Finlay, B. B., Ruschkowski, S. & Dedhar, S. Cytoskeletal rearrangements accompanying salmonella entry into epithelial cells. J. Cell Sci. 99, 283–296 (1991).

    PubMed  Google Scholar 

  139. Francis, C. L., Ryan, T. A., Jones, B. D., Smith, S. J. & Falkow, S. Ruffles induced by Salmonella and other stimuli direct macropinocytosis of bacteria. Nature 364, 639–642 (1993).

    Article  CAS  PubMed  Google Scholar 

  140. Karunasagar, I., Senghaas, B., Krohne, G. & Goebel, W. Ultrastructural study of Listeria monocytogenes entry into cultured human colonic epithelial cells. Infect. Immun. 62, 3554–3558 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Ray, K., Marteyn, B., Sansonetti, P. J. & Tang, C. M. Life on the inside: the intracellular lifestyle of cytosolic bacteria. Nat. Rev. Microbiol. 7, 333–340 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. Ly, K. T. & Casanova, J. E. Mechanisms of Salmonella entry into host cells. Cell. Microbiol. 9, 2103–2111 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Lhocine, N. et al. Apical invasion of intestinal epithelial cells by Salmonella typhimurium requires villin to remodel the brush border actin cytoskeleton. Cell Host Microbe 17, 164–177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhou, D., Mooseker, M. S. & Galan, J. E. An invasion-associated Salmonella protein modulates the actin-bundling activity of plastin. Proc. Natl Acad. Sci. USA 96, 10176–10181 (1999).

    Article  CAS  PubMed  Google Scholar 

  145. Frankel, G. et al. Generation of Escherichia coli intimin derivatives with differing biological activities using site-directed mutagenesis of the intimin C-terminus domain. Mol. Microbiol. 29, 559–570 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Shifrin, D. A. Jr, Crawley, S. W., Grega-Larson, N. E. & Tyska, M. J. Dynamics of brush border remodeling induced by enteropathogenic E. coli. Gut Microbes 5, 504–516 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Taylor, K. A., Luther, P. W. & Donnenberg, M. S. Expression of the EspB protein of enteropathogenic Escherichia coli within HeLa cells affects stress fibers and cellular morphology. Infect. Immun. 67, 120–125 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Iizumi, Y. et al. The enteropathogenic E. coli effector EspB facilitates microvillus effacing and antiphagocytosis by inhibiting myosin function. Cell Host Microbe 2, 383–392 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Mattoo, S., Alto, N. M. & Dixon, J. E. Subversion of myosin function by E. coli. Dev. Cell 14, 8–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Freeman, N. L. et al. Interaction of the enteropathogenic Escherichia coli protein, translocated intimin receptor (Tir), with focal adhesion proteins. Cell Motil. Cytoskeleton 47, 307–318 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Goosney, D. L. et al. Enteropathogenic E. coli translocated intimin receptor, Tir, interacts directly with α-actinin. Curr. Biol. 10, 735–738 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Cantarelli, V. V. et al. Cortactin is necessary for F-actin accumulation in pedestal structures induced by enteropathogenic Escherichia coli infection. Infect. Immun. 70, 2206–2209 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cantarelli, V. V. et al. Cortactin is essential for F-actin assembly in enteropathogenic Escherichia coli (EPEC)- and enterohaemorrhagic E. coli (EHEC)-induced pedestals and the α-helical region is involved in the localization of cortactin to bacterial attachment sites. Cell. Microbiol. 8, 769–780 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Gruenheid, S. et al. Enteropathogenic E. coli Tir binds Nck to initiate actin pedestal formation in host cells. Nat. Cell Biol. 3, 856–859 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Bommarius, B. et al. Enteropathogenic Escherichia coli Tir is an SH2/3 ligand that recruits and activates tyrosine kinases required for pedestal formation. Mol. Microbiol. 63, 1748–1768 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Nieto-Pelegrin, E., Kenny, B. & Martinez-Quiles, N. Nck adaptors, besides promoting N-WASP mediated actin-nucleation activity at pedestals, influence the cellular levels of enteropathogenic Escherichia coli Tir effector. Cell Adh. Migr. 8, 404–417 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Goluszko, P. et al. Decay-accelerating factor and cytoskeleton redistribution pattern in HeLa cells infected with recombinant Escherichia coli strains expressing Dr family of adhesins. Infect. Immun. 67, 3989–3997 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Peiffer, I. et al. Structural and functional lesions in brush border of human polarized intestinal Caco-2/TC7 cells infected by members of the Afa/Dr diffusely adhering family of Escherichia coli. Infect. Immun. 68, 5979–5990 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Van Loy, C. P., Sokurenko, E. V. & Moseley, S. L. The major structural subunits of Dr and F1845 fimbriae are adhesins. Infect. Immun. 70, 1694–1702 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Mounier, J., Vasselon, T., Hellio, R., Lesourd, M. & Sansonetti, P. J. Shigella flexneri enters human colonic Caco-2 epithelial cells through the basolateral pole. Infect. Immun. 60, 237–248 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Scott, K. G., Yu, L. C. & Buret, A. G. Role of CD8+ and CD4+ T lymphocytes in jejunal mucosal injury during murine giardiasis. Infect. Immun. 72, 3536–3542 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Troeger, H. et al. Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum. Gut 56, 328–335 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Lauwaet, T. et al. Proteinase inhibitors TPCK and TLCK prevent Entamoeba histolytica induced disturbance of tight junctions and microvilli in enteric cell layers in vitro. Int. J. Parasitol. 34, 785–794 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Moser, L. A., Carter, M. & Schultz-Cherry, S. Astrovirus increases epithelial barrier permeability independently of viral replication. J. Virol. 81, 11937–11945 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mendez, E. et al. Characterization of human astrovirus cell entry. J. Virol. 88, 2452–2460 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Chen, Y. Q. et al. The effect of enterohemorrhagic E. coli infection on the cell mechanics of host cells. PLoS ONE 9, e112137 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Heazlewood, C. K. et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sheng, Y. H. et al. MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli. Mucosal Immunol. 6, 557–568 (2013).

    Article  CAS  PubMed  Google Scholar 

  170. Sheng, Y. H. et al. The MUC13 cell-surface mucin protects against intestinal inflammation by inhibiting epithelial cell apoptosis. Gut 60, 1661–1670 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Murata, Y. et al. Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium. Proc. Natl Acad. Sci. USA 112, E4264–E4271 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Kobayashi, I. et al. Autoantibodies to villin occur frequently in IPEX, a severe immune dysregulation, syndrome caused by mutation of FOXP3. Clin. Immunol. 141, 83–89 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. DuPont, A. W. & DuPont, H. L. The intestinal microbiota and chronic disorders of the gut. Nat. Rev. Gastroenterol. Hepatol. 8, 523–531 (2011).

    Article  PubMed  Google Scholar 

  174. Jain, N. & Walker, W. A. Diet and host-microbial crosstalk in postnatal intestinal immune homeostasis. Nat. Rev. Gastroenterol. Hepatol. 12, 14–25 (2015).

    Article  CAS  PubMed  Google Scholar 

  175. Poley, J. R. Loss of the glycocalyx of enterocytes in small intestine: a feature detected by scanning electron microscopy in children with gastrointestinal intolerance to dietary protein. J. Pediatr. Gastroenterol. Nutr. 7, 386–394 (1988).

    Article  CAS  PubMed  Google Scholar 

  176. Kuitunen, P., Rapola, J., Savilahti, E. & Visakorpi, J. K. Response of the jejunal mucosa to cow's milk in the malabsorption syndrome with cow's milk intolerance. A light- and electron-microscopic study. Acta Paediatr. Scand. 62, 585–595 (1973).

    Article  CAS  PubMed  Google Scholar 

  177. Iancu, T. C. & Manov, I. Ultrastructural aspects of enterocyte defects in infancy and childhood. Ultrastruct. Pathol. 34, 117–125 (2010).

    Article  PubMed  Google Scholar 

  178. Shiner, M. & Birbeck, M. S. The microvilli of the small intestinal surface epithelium in coeliac disease and in idiopathic steatorrhoea. Gut 2, 277–284 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Magliocca, F. M. et al. Scanning electron microscopy of the small intestine during gluten-challenge in celiac disease. Arch. Histol. Cytol. 55 (Suppl.), 125–130 (1992).

    Article  PubMed  Google Scholar 

  180. Rostami, K. & Villanacci, V. Microscopic enteritis: novel prospect in coeliac disease clinical and immuno-histogenesis. Evolution in diagnostic and treatment strategies. Dig. Liver Dis. 41, 245–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. Mine, Y. & Zhang, J. W. Surfactants enhance the tight-junction permeability of food allergens in human intestinal epithelial Caco-2 cells. Int. Arch. Allergy Immunol. 130, 135–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  182. Secondulfo, M. et al. Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients. Dig. Liver Dis. 36, 35–45 (2004).

    Article  CAS  PubMed  Google Scholar 

  183. Hope, H. B. et al. Small intestinal malabsorption in chronic alcoholism determined by 13C-D-xylose breath test and microscopic examination of the duodenal mucosa. Scand. J. Gastroenterol. 45, 39–45 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. O'Brien, L. E., Zegers, M. M. & Mostov, K. E. Building epithelial architecture: insights from three-dimensional culture models. Nat. Rev. Mol. Cell Biol. 3, 531–537 (2002).

    Article  CAS  PubMed  Google Scholar 

  185. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  186. Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

    Article  CAS  PubMed  Google Scholar 

  187. McCracken, K. W., Howell, J. C., Wells, J. M. & Spence, J. R. Generating human intestinal tissue from pluripotent stem cells in vitro. Nat. Protoc. 6, 1920–1928 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  189. Fordham, R. P. et al. Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell 13, 734–744 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Wells, J. M. & Spence, J. R. How to make an intestine. Development 141, 752–760 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. le Digabel, J., Ghibaudo, M., Trichet, L., Richert, A. & Ladoux, B. Microfabricated substrates as a tool to study cell mechanotransduction. Med. Biol. Eng. Comput. 48, 965–976 (2010).

    Article  PubMed  Google Scholar 

  192. Sung, J. H., Yu, J., Luo, D., Shuler, M. L. & March, J. C. Microscale 3D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model. Lab Chip 11, 389–392 (2011).

    Article  CAS  PubMed  Google Scholar 

  193. Huh, D. et al. Microfabrication of human organs-on-chips. Nat. Protoc. 8, 2135–2157 (2013).

    Article  CAS  PubMed  Google Scholar 

  194. Pearl, M., Fishkind, D., Mooseker, M., Keene, D. & Keller, T. 3rd Studies on the spectrin-like protein from the intestinal brush border, TW 260/240, and characterization of its interaction with the cytoskeleton and actin. J. Cell Biol. 98, 66–78 (1984).

    Article  CAS  PubMed  Google Scholar 

  195. Gunning, P. W., Hardeman, E. C., Lappalainen, P. & Mulvihill, D. P. Tropomyosin — master regulator of actin filament function in the cytoskeleton. J. Cell Sci. 128, 2965–2974 (2015).

    Article  CAS  PubMed  Google Scholar 

  196. Oriolo, A. S., Wald, F. A., Ramsauer, V. P. & Salas, P. J. Intermediate filaments: a role in epithelial polarity. Exp. Cell Res. 313, 2255–2264 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Schnell, U., Cirulli, V. & Giepmans, B. N. EpCAM: structure and function in health and disease. Biochim. Biophys. Acta 1828, 1989–2001 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Sivagnanam, M. et al. Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology 135, 429–437 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Sivagnanam, M. et al. Case of syndromic tufting enteropathy harbors SPINT2 mutation seen in congenital sodium diarrhea. Clin. Dysmorphol. 19, 48 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Tocchetti, A. et al. Loss of the actin remodeler Eps8 causes intestinal defects and improved metabolic status in mice. PLoS ONE 5, e9468 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are supported by grants from the GEFLUC Paris-Ile de France “Les entreprises contre le cancer” (to D.D.), from “Initiatives d'excellence» (Idex ANR-11-IDEX-0005-02) - Labex Who Am I? (ANR-11-LABX-0071) (to D.D.), from “Postes accueil AP-HP – CNRS” (PhD fellowhip for to J.S.) and from the “Assistance Publique – Hôpitaux de Paris, AP-HP” (Projets Hospitaliers de Recherche Clinique (PHRC) DEI (#AOM07059) and AMVILLO (#AOM09136) grants, to D.D. in collaboration with O. Goulet).

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  1. Cell Adhesion and Mechanics, Institut Jacques Monod, CNRS UMR7592, Paris Diderot University, Paris, France

    Delphine Delacour

  2. Paediatric Gastroenterology Department, Hôpital Necker-Enfants Malades, Paris Descartes University, Sorbonne Paris Cité, Paris, France

    Julie Salomon

  3. Institut Curie, Centre de Recherche, CNRS UMR 144, Paris, France

    Sylvie Robine & Daniel Louvard

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Delacour, D., Salomon, J., Robine, S. et al. Plasticity of the brush border — the yin and yang of intestinal homeostasis. Nat Rev Gastroenterol Hepatol 13, 161–174 (2016). https://doi.org/10.1038/nrgastro.2016.5

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