Gastroenterology
Volume 138, Issue 5 , Pages 1681-1696 , May 2010

Leucine-Rich Repeat-Containing G-Protein-Coupled Receptors as Markers of Adult Stem Cells

  • Nick Barker

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Nick Barker, PhD, Hubrecht Institute, Uppsalalaan 8, 3584CT Utrecht, The Netherlands. fax: +31 30 2121801
  • ,
  • Hans Clevers

Received 3 February 2010 ,Accepted 5 March 2010.

References 

  1. Tumbar T, Guasch G, Greco V, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303:359–363
  2. Kiel MJ, He S, Ashkenazi R, et al. Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature. 2007;449:238–242
  3. Alison MR, Islam S. Attributes of adult stem cells. J Pathol. 2009;217:144–160
  4. Pinto D, Gregorieff A, Begthel H, et al. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003;17:1709–1713
  5. Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19:379–383
  6. Hoffman J, Kuhnert F, Davis CR, et al. Wnts as essential growth factors for the adult small intestine and colon. Cell Cycle. 2004;3:554–557
  7. Korinek V, Barker N, Morin PJ, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science. 1997;275:1784–1787
  8. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–1790
  9. van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002;111:241–250
  10. Van der Flier LG, Sabates-Bellver J, Oving I, et al. The intestinal Wnt/TCF signature. Gastroenterology. 2007;132:628–632
  11. van Es JH, Jay P, Gregorieff A, et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol. 2005;7:381–386
  12. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–1007
  13. Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine (V. Unitarian theory of the origin of the four epithelial cell types). Am J Anat. 1974;141:537–561
  14. Giannakis M, Stappenbeck TS, Mills JC, et al. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J Biol Chem. 2006;281:11292–11300
  15. Barker N, Clevers H. Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology. 2007;133:1755–1760
  16. Hsu SY, Liang SG, Hsueh AJ. Characterization of two Lgr genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol. 1998;12:1830–1845
  17. Hsu SY, Kudo M, Chen T, et al. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (Lgr): identification of Lgr6 and Lgr7 and the signaling mechanism for Lgr7. Mol Endocrinol. 2000;14:1257–1271
  18. Nothacker HP, Grimmelikhuijzen CJ. Molecular cloning of a novel, putative G protein-coupled receptor from sea anemones structurally related to members of the FSH, TSH, LH/CG receptor family from mammals. Biochem Biophys Res Commun. 1993;197:1062–1069
  19. Herpin A, Badariotti F, Rodet F, et al. Molecular characterization of a new leucine-rich repeat-containing G protein-coupled receptor from a bivalve mollusc: evolutionary implications. Biochim Biophys Acta. 2004;1680:137–144
  20. Tensen CP, Van Kesteren ER, Planta RJ, et al. A G protein-coupled receptor with low density lipoprotein-binding motifs suggests a role for lipoproteins in G-linked signal transduction. Proc Natl Acad Sci U S A. 1994;91:4816–4820
  21. Kudo M, Chen T, Nakabayashi K, et al. The nematode leucine-rich repeat-containing, G protein-coupled receptor (Lgr) protein homologous to vertebrate gonadotropin and thyrotropin receptors is constitutively active in mammalian cells. Mol Endocrinol. 2000;14:272–284
  22. Hauser F, Nothacker HP, Grimmelikhuijzen CJ. Molecular cloning, genomic organization, and developmental regulation of a novel receptor from Drosophila melanogaster structurally related to members of the thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone/choriogonadotropin receptor family from mammals. J Biol Chem. 1997;272:1002–1010
  23. Nishi S, Hsu SY, Zell K, et al. Characterization of two fly Lgr (leucine-rich repeat-containing, G protein-coupled receptor) proteins homologous to vertebrate glycoprotein hormone receptors: constitutive activation of wild-type fly Lgr1 but not Lgr2 in transfected mammalian cells. Endocrinology. 2000;141:4081–4090
  24. Vassart G, Pardo L, Costagliola S. A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci. 2004;29:119–126
  25. Kajava AV. Structural diversity of leucine-rich repeat proteins. J Mol Biol. 1998;277:519–527
  26. Vitt UA, Hsu SY, Hsueh AJ. Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol. 2001;15:681–694
  27. Hsu SY, Nakabayashi K, Nishi S, et al. Activation of orphan receptors by the hormone relaxin. Science. 2002;295:671–674
  28. Kumagai J, Hsu SY, Matsumi H, et al. INSL3/Leydig insulin-like peptide activates the Lgr8 receptor important in testis descent. J Biol Chem. 2002;277:31283–31286
  29. Baker JD, Truman JW. Mutations in the Drosophila glycoprotein hormone receptor, rickets, eliminate neuropeptide-induced tanning and selectively block a stereotyped behavioral program. J Exp Biol. 2002;205:2555–2565
  30. Honegger HW, Market D, Pierce LA, et al. Cellular localization of bursicon using antisera against partial peptide sequences of this insect cuticle-sclerotizing neurohormone. J Comp Neurol. 2002;452:163–177
  31. Dewey EM, McNabb SL, Ewer J, et al. Identification of the gene encoding bursicon, an insect neuropeptide responsible for cuticle sclerotization and wing spreading. Curr Biol. 2004;14:1208–1213
  32. Luo CW, Dewey EM, Sudo S, et al. Bursicon, the insect cuticle-hardening hormone, is a heterodimeric cystine knot protein that activates G protein-coupled receptor Lgr2. Proc Natl Acad Sci U S A. 2005;102:2820–2825
  33. Mendive FM, Van Loy T, Claeysen S, et al. Drosophila molting neurohormone bursicon is a heterodimer and the natural agonist of the orphan receptor DLgr2. FEBS Lett. 2005;579:2171–2176
  34. Avsian-Kretchmer O, Hsueh AJ. Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists. Mol Endocrinol. 2004;18:1–12
  35. Mazerbourg S, Bouley DM, Sudo S, et al. Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol. 2004;18:2241–2254
  36. Van Schoore G, Mendive F, Pochet R, et al. Expression pattern of the orphan receptor Lgr4/GPR48 gene in the mouse. Histochem Cell Biol. 2005;124:35–50
  37. Leighton PA, Mitchell KJ, Goodrich LV, et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature. 2001;410:174–179
  38. Mendive F, Laurent P, Van Schoore G, et al. Defective postnatal development of the male reproductive tract in Lgr4 knockout mice. Dev Biol. 2006;290:421–434
  39. Li XY, Lu Y, Sun HY, et al. G protein-coupled receptor 48 upregulates estrogen receptor alpha expression via cAMP/PKA signaling in the male reproductive tract. Development. 2010;137:151–157
  40. Hoshii T, Takeo T, Nakagata N, et al. Lgr4 regulates the postnatal development and integrity of male reproductive tracts in mice. Biol Reprod. 2007;76:303–313
  41. Yamashita R, Takegawa Y, Sakumoto M, et al. Defective development of the gall bladder and cystic duct in Lgr4- hypomorphic mice. Dev Dyn. 2009;238:993–1000
  42. Song H, Luo J, Luo W, et al. Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem. 2008;283:36687–36697
  43. Weng J, Luo J, Cheng X, et al. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci U S A. 2008;105:6081–6086
  44. Luo J, Zhou W, Zhou X, et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009;136:2747–2756
  45. Kato S, Matsubara M, Matsuo T, et al. Leucine-rich repeat-containing G protein-coupled receptor-4 (Lgr4, Gpr48) is essential for renal development in mice. Nephron Exp Nephrol. 2006;104:e63–e75
  46. Kato S, Mohri Y, Matsuo T, et al. Eye-open at birth phenotype with reduced keratinocyte motility in Lgr4 null mice. FEBS Lett. 2007;581:4685–4690
  47. Jin C, Yin F, Lin M, et al. GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Invest Ophthalmol Vis Sci. 2008;49:4245–4253
  48. Mohri Y, Kato S, Umezawa A, et al. Impaired hair placode formation with reduced expression of hair follicle-related genes in mice lacking Lgr4. Dev Dyn. 2008;237:2235–2242
  49. McClanahan T, Koseoglu S, Smith K, et al. Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol Ther. 2006;5:419–426
  50. Yamamoto Y, Sakamoto M, Fujii G, et al. Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology. 2003;37:528–533
  51. Zucman-Rossi J, Benhamouche S, Godard C, et al. Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas. Oncogene. 2007;26:774–780
  52. Tanese K, Fukuma M, Yamada T, et al. G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. Am J Pathol. 2008;173:835–843
  53. Krusche CA, Kroll T, Beier HM, et al. Expression of leucine-rich repeat-containing G-protein-coupled receptors in the human cyclic endometrium. Fertil Steril. 2007;87:1428–1437
  54. Morita H, Mazerbourg S, Bouley DM, et al. Neonatal lethality of Lgr5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol. 2004;24:9736–9743
  55. Garcia MI, Ghiani M, Lefort A, et al. Lgr5 deficiency deregulates Wnt signaling and leads to precocious Paneth cell differentiation in the fetal intestine. Dev Biol. 2009;331:58–67
  56. Barker N, van de Wetering M, Clevers H. The intestinal stem cell. Genes Dev. 2008;22:1856–1864
  57. Potten CS. Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature. 1977;269:518–521
  58. Potten CS, Kovacs L, Hamilton E. Continuous labelling studies on mouse skin and intestine. Cell Tissue Kinet. 1974;7:271–283
  59. Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet. 2008;40:915–920
  60. Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine (I. Columnar cell). Am J Anat. 1974;141:461–479
  61. Bjerknes M, Cheng H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology. 1999;116:7–14
  62. Bjerknes M, Cheng H. The stem-cell zone of the small intestinal epithelium (I. Evidence from Paneth cells in the adult mouse). Am J Anat. 1981;160:51–63
  63. Bjerknes M, Cheng H. The stem-cell zone of the small intestinal epithelium (III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse). Am J Anat. 1981;160:77–91
  64. Barker N, van Es JH, Jaks V, et al. Very long-term self-renewal of small intestine, colon, and hair follicles from cycling Lgr5+ve stem cells. Cold Spring Harb Symp Quant Biol. 2008;73:351–356
  65. Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999;21:70–71
  66. Lee ER, Trasler J, Dwivedi S, et al. Division of the mouse gastric mucosa into zymogenic and mucous regions on the basis of gland features. Am J Anat. 1982;164:187–207
  67. Lee ER, Leblond CP. Dynamic histology of the antral epithelium in the mouse stomach: IV. Ultrastructure and renewal of gland cells. Am J Anat. 1985;172:241–259
  68. Lee ER, Leblond CP. Dynamic histology of the antral epithelium in the mouse stomach: II. Ultrastructure and renewal of isthmal cells. Am J Anat. 1985;172:205–224
  69. Karam SM, Leblond CP. Identifying and counting epithelial cell types in the “corpus” of the mouse stomach. Anat Rec. 1992;232:231–246
  70. Bjerknes M, Cheng H. Multipotential stem cells in adult mouse gastric epithelium. Am J Physiol Gastrointest Liver Physiol. 2002;283:G767–G777
  71. McDonald SA, Greaves LC, Gutierrez-Gonzalez L, et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology. 2008;134:500–510
  72. Qiao XT, Ziel JW, McKimpson W, et al. Prospective identification of a multilineage progenitor in murine stomach epithelium. Gastroenterology. 2007;133:1989–1998
  73. Hattori T, Fujita S. Tritiated thymidine autoradiographic study on cellular migration in the gastric gland of the golden hamster. Cell Tissue Res. 1976;172:171–184
  74. Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach (V. Behavior of entero-endocrine and caveolated cells: general conclusions on cell kinetics in the oxyntic epithelium). Anat Rec. 1993;236:333–340
  75. Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach (III. Inward migration of neck cells followed by progressive transformation into zymogenic cells). Anat Rec. 1993;236:297–313
  76. Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach (II. Outward migration of pit cells). Anat Rec. 1993;236:280–296
  77. Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach (I. Identification of proliferative cell types and pinpointing of the stem cell). Anat Rec. 1993;236:259–279
  78. Nomura S, Esumi H, Job C, et al. Lineage and clonal development of gastric glands. Dev Biol. 1998;204:124–135
  79. Tatematsu M, Fukami H, Yamamoto M, et al. Clonal analysis of glandular stomach carcinogenesis in C3H/HeN<==>BALB/c chimeric mice treated with N-methyl-N-nitrosourea. Cancer Lett. 1994;83:37–42
  80. Barker N, Huch M, Kujala P, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6:25–36
  81. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–850
  82. Alonso L, Fuchs E. The hair cycle. J Cell Sci. 2006;119:391–393
  83. Blanpain C, Lowry WE, Geoghegan A, et al. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118:635–648
  84. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61:1329–1337
  85. Morris RJ, Liu Y, Marles L, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol. 2004;22:411–417
  86. Trempus CS, Morris RJ, Bortner CD, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol. 2003;120:501–511
  87. Braun KM, Niemann C, Jensen UB, et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in whole mounts of mouse epidermis. Development. 2003;130:5241–5255
  88. Jaks V, Barker N, Kasper M, et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet. 2008;40:1291–1299
  89. Snippert HJ, Kasper M, Jaks V, et al. Lgr6 stem cells generate all cell lineages of the skin. Science. 2010;327:1385–1389
  90. Quigley DA, To MD, Perez-Losada J, et al. Genetic architecture of mouse skin inflammation and tumour susceptibility. Nature. 2009;458:505–508
  91. Fuchs E, Horsley V. More than one way to skin. Genes Dev. 2008;22:976–985
  92. Ito M, Liu Y, Yang Z, et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11:1351–1354
  93. Ito M, Yang Z, Andl T, et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007;447:316–320
  94. Potten CS, Booth C, Tudor GL, et al. Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation. 2003;71:28–41
  95. Zhu L, Gibson P, Currle DS, et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature. 2009;457:603–607
  96. Snippert HJ, van Es JH, van den Born M, et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology. 2009;136:2187e1–2194e1
  97. Montgomery RK, Shivdasani RA. Prominin1 (CD133) as an intestinal stem cell marker: promise and nuance. Gastroenterology. 2009;136:2051–2054
  98. Gerbe F, Brulin B, Makrini L, et al. DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology. 2009;137:2179–2181
  99. Van der Flier LG, van Gijn ME, Hatzis P, et al. Transcription factor Achaete scute-like 2 (Ascl2) controls intestinal stem cell fate. Cell. 2009;136:903–912
  100. van der Flier LG, Haegebarth A, Stange DE, et al. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology. 2009;137:15–17
  101. Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–265
  102. Evans GS, Flint N, Somers AS, et al. The development of a method for the preparation of rat intestinal epithelial cell primary cultures. J Cell Sci. 1992;101:219–231
  103. Fukamachi H. Proliferation and differentiation of fetal rat intestinal epithelial cells in primary serum-free culture. J Cell Sci. 1992;103:511–519
  104. Perreault N, Jean-Francois B. Use of the dissociating enzyme thermolysin to generate viable human normal intestinal epithelial cell cultures. Exp Cell Res. 1996;224:354–364
  105. Whitehead RH, Demmler K, Rockman SP, et al. Clonogenic growth of epithelial cells from normal colonic mucosa from both mice and humans. Gastroenterology. 1999;117:858–865
  106. Bjerknes M, Cheng H. Intestinal epithelial stem cells and progenitors. Methods Enzymol. 2006;419:337–383
  107. Kim KA, Kakitani M, Zhao J, et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science. 2005;309:1256–1259
  108. Dignass AU, Sturm A. Peptide growth factors in the intestine. Eur J Gastroenterol Hepatol. 2001;13:763–770
  109. Haramis AP, Begthel H, van den Born M, et al. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science. 2004;303:1684–1686
  110. Hofmann C, Obermeier F, Artinger M, et al. Cell-cell contacts prevent anoikis in primary human colonic epithelial cells. Gastroenterology. 2007;132:587–600
  111. Sasaki T, Giltay R, Talts U, et al. Expression and distribution of laminin alpha1 and alpha2 chains in embryonic and adult mouse tissues: an immunochemical approach. Exp Cell Res. 2002;275:185–199
  112. Ootani A, Li X, Sangiorgi E, et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. 2009;15:701–706
  113. Barker N, Ridgway RA, van Es JH, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–611

 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(10)00336-7

doi: 10.1053/j.gastro.2010.03.002

Gastroenterology
Volume 138, Issue 5 , Pages 1681-1696 , May 2010