Gastroenterology
Volume 137, Issue 1 , Pages 62-79 , July 2009

Mechanisms of Liver Development: Concepts for Understanding Liver Disorders and Design of Novel Therapies

  • Frédéric P. Lemaigre

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Frédéric P. Lemaigre, MD, PhD, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75/7529, 1200 Brussels, Belgium. fax (32) 2 764 7507

Received 10 February 2009 ,Accepted 18 March 2009.

References 

  1. Tremblay KD, Zaret KS. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Dev Biol. 2005;280:87–99
  2. Zaret KS. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet. 2008;9:329–340
  3. Gualdi R, Bossard P, Zheng M, et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 1996;10:1670–1682
  4. Jung J, Zheng M, Goldfarb M, et al. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science. 1999;284:1998–2003
  5. Bossard P, Zaret KS. GATA transcription factors as potentiators of gut endoderm differentiation. Development. 1998;125:4909–4917
  6. Cirillo LA, Lin FR, Cuesta I, et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell. 2002;9:279–289
  7. Lee CS, Friedman JR, Fulmer JT, et al. The initiation of liver development is dependent on Foxa transcription factors. Nature. 2005;435:944–947
  8. Lokmane L, Haumaitre C, Garcia-Villalba P, et al. Crucial role of vHNF1 in vertebrate hepatic specification. Development. 2008;135:2777–2786
  9. Calmont A, Wandzioch E, Tremblay KD, et al. An FGF response pathway that mediates hepatic gene induction in embryonic endoderm cells. Dev Cell. 2006;11:339–348
  10. Serls AE, Doherty S, Parvatiyar P, et al. Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development. 2005;132:35–47
  11. Huang H, Ruan H, Aw MY, et al. Mypt1-mediated spatial positioning of Bmp2-producing cells is essential for liver organogenesis. Development. 2008;135:3209–3218
  12. Shin D, Shin CH, Tucker J, et al. Bmp and Fgf signaling are essential for liver specification in zebrafish. Development. 2007;134:2041–2050
  13. Chung WS, Shin CH, Stainier DY. Bmp2 signaling regulates the hepatic versus pancreatic fate decision. Dev Cell. 2008;15:738–748
  14. Zhang W, Yatskievych TA, Baker RK, et al. Regulation of Hex gene expression and initial stages of avian hepatogenesis by Bmp and Fgf signaling. Dev Biol. 2004;268:312–326
  15. McLin VA, Rankin SA, Zorn AM. Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development. 2007;134:2207–2217
  16. Finley KR, Tennessen J, Shawlot W. The mouse secreted frizzled-related protein 5 gene is expressed in the anterior visceral endoderm and foregut endoderm during early post-implantation development. Gene Expr Patterns. 2003;3:681–684
  17. Li Y, Rankin SA, Sinner D, et al. Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev. 2008;22:3050–3063
  18. Ober EA, Verkade H, Field HA, et al. Mesodermal Wnt2b signalling positively regulates liver specification. Nature. 2006;442:688–691
  19. Bort R, Signore M, Tremblay K, et al. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev Biol. 2006;290:44–56
  20. Shiojiri N, Sugiyama Y. Immunolocalization of extracellular matrix components and integrins during mouse liver development. Hepatology. 2004;40:346–355
  21. Martinez-Barbera JP, Clements M, Thomas P, et al. The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development. 2000;127:2433–2445
  22. Keng VW, Yagi H, Ikawa M, et al. Homeobox gene Hex is essential for onset of mouse. Biochem Biophys Res Commun. 2000;276:1155–1161
  23. Zhao R, Watt AJ, Li J, et al. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol. 2005;25:2622–2631
  24. Sosa-Pineda B, Wigle JT, Oliver G. Hepatocyte migration during liver development requires Prox1. Nat Genet. 2000;25:254–255
  25. Lüdtke TH, Christoffels VM, Petry M, et al. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology. 2009;49:969–978
  26. Margagliotti S, Clotman F, Pierreux CE, et al. The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol. 2007;311:579–589
  27. Margagliotti S, Clotman F, Pierreux CE, et al. Role of metalloproteinases at the onset of liver development. Dev Growth Differ. 2008;50:331–338
  28. Matsumoto K, Yoshitomi H, Rossant J, et al. Liver organogenesis promoted by endothelial cells prior to vascular function. Science. 2001;294:559–563
  29. Watt AJ, Zhao R, Li J, et al. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol. 2007;7:37
  30. Rossi JM, Dunn NR, Hogan BL, et al. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev. 2001;15:1998–2009
  31. Tanimizu N, Miyajima A. Molecular mechanism of liver development and regeneration. Int Rev Cytol. 2007;259:1–48
  32. Hilberg F, Aguzzi A, Howells N, et al. c-jun is essential for normal mouse development and hepatogenesis. Nature. 1993;365:179–181
  33. Nishina H, Vaz C, Billia P, et al. Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development. 1999;126:505–516
  34. Schmidt C, Bladt F, Goedecke S, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699–702
  35. Uehara Y, Minowa O, Mori C, et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995;373:702–705
  36. Bladt F, Riethmacher D, Isenmann S, et al. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995;376:768–771
  37. Breitwieser W, Lyons S, Flenniken AM, et al. Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. Genes Dev. 2007;21:2069–2082
  38. Weinstein M, Monga SP, Liu Y, et al. Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-integrin to promote normal liver development. Mol Cell Biol. 2001;21:5122–5131
  39. Fässler R, Meyer M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 1995;9:1896–1908
  40. Enomoto H, Yoshida K, Kishima Y, et al. Hepatoma-derived growth factor is highly expressed in developing liver and promotes fetal hepatocyte proliferation. Hepatology. 2002;36:1519–1527
  41. Gallitzendoerfer R, Abouzied MM, Hartmann D, et al. Hepatoma-derived growth factor (HDGF) is dispensable for normal mouse development. Dev Dyn. 2008;237:1875–1885
  42. Zeng G, Awan F, Otruba W, et al. Wnt'er in liver: expression of Wnt and frizzled genes in mouse. Hepatology. 2007;45:195–204
  43. Matsumoto K, Miki R, Nakayama M, et al. Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. Dev Biol. 2008;319:234–247
  44. Tan X, Yuan Y, Zeng G, et al. Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology. 2008;47:1667–1679
  45. Suksaweang S, Lin CM, Jiang TX, et al. Morphogenesis of chicken liver: identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. Dev Biol. 2004;266:109–122
  46. Monga SP, Mars WM, Pediaditakis P, et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002;62:2064–2071
  47. Berg T, Rountree CB, Lee L, et al. Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via beta-catenin activation. Hepatology. 2007;46:1187–1197
  48. Ijpenberg A, Pérez-Pomares JM, Guadix JA, et al. Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis. Dev Biol. 2007;312:157–170
  49. Doi TS, Marino MW, Takahashi T, et al. Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci U S A. 1999;96:2994–2999
  50. Piazzolla D, Meissl K, Kucerova L, et al. Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling. J Cell Biol. 2005;171:1013–1022
  51. Kamiya A, Kakinuma S, Onodera M, et al. Prospero-related homeobox 1 and liver receptor homolog 1 coordinately regulate long-term proliferation of murine fetal hepatoblasts. Hepatology. 2008;48:252–264
  52. Krupczak-Hollis K, Wang X, Kalinichenko VV, et al. The mouse Forkhead Box m1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis. Dev Biol. 2004;276:74–88
  53. Reimold AM, Etkin A, Clauss I, et al. An essential role in liver development for transcription factor XBP-1. Genes Dev. 2000;14:152–157
  54. Nakayama M, Matsumoto K, Tatsumi N, et al. Id3 is important for proliferation and differentiation of the hepatoblasts during the chick liver development. Mech Dev. 2006;123:580–590
  55. Hentsch B, Lyons I, Li R, et al. Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut. Genes Dev. 1996;10:70–79
  56. Giroux S, Charron J. Defective development of the embryonic liver in N-myc-deficient mice. Dev Biol. 1998;195:16–28
  57. Li J, Ning G, Duncan SA. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev. 2000;14:464–474
  58. Van Eyken P, Sciot R, Callea F, et al. The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology. 1988;8:1586–1595
  59. Antoniou A, Raynaud P, Cordi S, et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology (in press).
  60. Suzuki A, Sekiya S, Büscher D, et al. Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development. 2008;135:1589–1595
  61. Clotman F, Jacquemin P, Plumb-Rudewiez N, et al. Control of liver cell fate decision by a gradient of TGFβ signaling modulated by Onecut transcription factors. Genes Dev. 2005;19:1849–1854
  62. Clotman F, Lannoy VJ, Reber M, et al. The onecut transcription factor Hnf6 is required for normal development of the biliary tract. Development. 2002;129:1819–1828
  63. Suzuki A, Iwama A, Miyashita H, et al. Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development. 2003;130:2513–2524
  64. Hunter MP, Wilson CM, Jiang X, et al. The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev Biol. 2007;308:355–367
  65. Zhang L, Theise N, Chua M, et al. The stem cell niche of human livers: symmetry between development and regeneration. Hepatology. 2008;48:1598–1607
  66. Simper-Ronan R, Brilliant K, Flanagan D, et al. Cholangiocyte marker-positive and -negative fetal liver cells differ significantly in their ability to regenerate the livers of adult rats exposed to retrorsine. Development. 2006;133:4269–4279
  67. Tanimizu N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004;117:3165–3174
  68. Yanai M, Tatsumi N, Hasunuma N, et al. FGF signaling segregates biliary cell-lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro. Dev Dyn. 2008;237:1268–1283
  69. Ader T, Norel R, Levoci L, et al. Transcriptional profiling implicates TGFbeta/BMP and Notch signaling pathways in ductular differentiation of fetal murine hepatoblasts. Mech Dev. 2006;123:177–194
  70. Hussain SZ, Sneddon T, Tan X, et al. Wnt impacts growth and differentiation in ex vivo liver development. Exp Cell Res. 2004;292:157–169
  71. Monga SP, Monga HK, Tan X, et al. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology. 2003;124:202–216
  72. Decaens T, Godard C, de Reyniès A, et al. Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology. 2008;47:247–258
  73. Wandzioch E, Kolterud A, Jacobsson M, et al. Lhx2-/- mice develop liver fibrosis. Proc Natl Acad Sci U S A. 2004;101:16549–16554
  74. Jochheim A, Cieslak A, Hillemann T, et al. Multi-stage analysis of differential gene expression in BALB/C mouse liver development by high-density microarrays. Differentiation. 2003;71:62–72
  75. Kelley-Loughnane N, Sabla GE, Ley-Ebert C, et al. Independent and overlapping transcriptional activation during liver development and regeneration in mice. Hepatology. 2002;35:525–534
  76. Petkov PM, Zavadil J, Goetz D, et al. Gene expression pattern in hepatic stem/progenitor cells during rat fetal development using complementary DNA microarrays. Hepatology. 2004;39:617–627
  77. Kyrmizi I, Hatzis P, Katrakili N, et al. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev. 2006;20:2293–2305
  78. Beaudry JB, Pierreux CE, Hayhurst GP, et al. Threshold levels of hepatocyte nuclear factor 6 (HNF-6) acting in synergy with HNF-4 and PGC-1alpha are required for time-specific gene expression during liver development. Mol Cell Biol. 2006;26:6037–6046
  79. Yoshida Y, Hughes DE, Rausa FM, et al. C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells. Hepatology. 2006;43:276–286
  80. Schrem H, Klempnauer J, Borlak J. Liver-enriched transcription factors in liver function and development (Part I: the hepatocyte nuclear factor network and liver-specific gene expression). Pharmacol Rev. 2002;54:129–158
  81. Schrem H, Klempnauer J, Borlak J. Liver-enriched transcription factors in liver function and development (Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation). Pharmacol Rev. 2004;56:291–330
  82. Costa RH, Kalinichenko VV, Holterman AX, et al. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003;38:1331–1347
  83. Odom DT, Zizlsperger N, Gordon DB, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303:1378–1381
  84. Odom DT, Dowell RD, Jacobsen ES, et al. Core transcriptional regulatory circuitry in human hepatocytes. Mol Syst Biol. 2006;2:2006–0017
  85. Coffinier C, Gresh L, Fiette L, et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development. 2002;129:1829–1838
  86. Friedman JR, Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006;63:2317–2328
  87. Fayard E, Auwerx J, Schoonjans K. LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends Cell Biol. 2004;14:250–260
  88. Lee YK, Moore DD. Liver receptor homolog-1, an emerging metabolic modulator. Front Biosci. 2008;13:5950–5958
  89. Lahuna O, Fernandez L, Karlsson H, et al. Expression of hepatocyte nuclear factor 6 in rat liver is sex-dependent and regulated by growth hormone. Proc Natl Acad Sci U S A. 1997;94:12309–12313
  90. Pierreux CE, Stafford J, Demonte D, et al. Antiglucocorticoid activity of hepatocyte nuclear factor-6. Proc Natl Acad Sci U S A. 1999;96:8961–8966
  91. Lannoy VJ, Decaux JF, Pierreux CE, et al. Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6. Diabetologia. 2002;45:1136–1141
  92. Wang M, Tan Y, Costa RH, et al. In vivo regulation of murine CYP7A1 by HNF-6: a novel mechanism for diminished CYP7A1 expression in biliary obstruction. Hepatology. 2004;40:600–608
  93. Tan Y, Yoshida Y, Hughes DE, et al. Increased expression of hepatocyte nuclear factor 6 stimulates hepatocyte proliferation during mouse liver regeneration. Gastroenterology. 2006;130:1283–1300
  94. Lekstrom-Himes J, Xanthopoulos KG. Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem. 1998;273:28545–28548
  95. Parviz F, Matullo C, Garrison WD, et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet. 2003;34:292–296
  96. Qu X, Lam E, Doughman YQ, et al. Cited2, a coactivator of HNF4alpha, is essential for liver development. EMBO J. 2007;26:4445–4456
  97. Battle MA, Konopka G, Parviz F, et al. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci U S A. 2006;103:8419–8424
  98. Luebke-Wheeler J, Zhang K, Battle M, et al. Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H. Hepatology. 2008;48:1242–1250
  99. Hayhurst GP, Strick-Marchand H, Mulet C, et al. Morphogenetic competence of HNF4 alpha-deficient mouse hepatic cells. J Hepatol. 2008;49:384–395
  100. Perincheri S, Dingle RW, Peterson ML, et al. Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene. Proc Natl Acad Sci U S A. 2005;102:396–401
  101. Xie Z, Zhang H, Tsai W, et al. Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver. Proc Natl Acad Sci U S A. 2008;105:10859–10864
  102. Tatarakis A, Margaritis T, Martinez-Jimenez CP, et al. Dominant and redundant functions of TFIID involved in the regulation of hepatic genes. Mol Cell. 2008;31:531–543
  103. Gresh L, Bourachot B, Reimann A, et al. The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation. EMBO J. 2005;24:3313–3324
  104. Kamiya A, Kinoshita T, Ito Y, et al. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J. 1999;18:2127–2136
  105. Ito Y, Matsui T, Kamiya A, et al. Retroviral gene transfer of signaling molecules into murine fetal hepatocytes defines distinct roles for the STAT3 and ras pathways during hepatic development. Hepatology. 2000;32:1370–1376
  106. Anzai H, Kamiya A, Shirato H, et al. Impaired differentiation of fetal hepatocytes in homozygous jumonji mice. Mech Dev. 2003;120:791–800
  107. Tanaka M, Hirabayashi Y, Sekiguchi T, et al. Targeted disruption of oncostatin M receptor results in altered hematopoiesis. Blood. 2003;102:3154–3162
  108. Kamiya A, Gonzalez FJ. TNF-alpha regulates mouse fetal hepatic maturation induced by oncostatin M and extracellular matrices. Hepatology. 2004;40:527–536
  109. Suzuki T, Kanai Y, Hara T, et al. Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development. Mol Cell Biol. 2006;26:6149–6156
  110. Sakaguchi TF, Sadler KC, Crosnier C, et al. Endothelial signals modulate hepatocyte apicobasal polarization in zebrafish. Curr Biol. 2008;18:1565–1571
  111. Hart SN, Cui Y, Klaassen CD, et al. Three patterns of cytochrome P450 gene expression during liver maturation in mice. Drug Metab Dispos. 2009;37:116–121
  112. Kamiya A, Kinoshita T, Miyajima A. Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways. FEBS Lett. 2001;492:90–94
  113. Katz N, Jungermann K. Autoregulatory shift from fructolysis to lactate gluconeogenisis in rat hepatocyte suspensions (The problem of metabolic zonation of liver parenchyma). Hoppe Seylers Z Physiol Chem. 1976;357:359–375
  114. Jungermann K, Katz N. Functional specialization of different hepatocyte populations. Physiol Rev. 1989;69:708–764
  115. Gebhardt R, Baldysiak-Figiel A, Krügel V, et al. Hepatocellular expression of glutamine synthetase: an indicator of morphogen actions as master regulators of zonation in adult liver. Prog Histochem Cytochem. 2007;41:201–266
  116. Stanulović VS, Kyrmizi I, Kruithof-de Julio M, et al. Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes. Hepatology. 2007;45:433–444
  117. Benhamouche S, Decaens T, Godard C, et al. Apc tumor suppressor gene is the ”zonation-keeper” of mouse liver. Dev Cell. 2006;10:759–770
  118. Zern MA. Cell transplantation to replace whole liver transplantation. Gastroenterology. 2009;136:767–769
  119. Lavon N, Benvenisty N. Study of hepatocyte differentiation using embryonic stem cells. J Cell Biochem. 2005;96:1193–1202
  120. Gouon-Evans V, Boussemart L, Gadue P, et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol. 2006;24:1402–1411
  121. Hay DC, Fletcher J, Payne C, et al. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci U S A. 2008;105:12301–12306
  122. Roskams T, Desmet V. Embryology of extra- and intrahepatic bile ducts, the ductal plate. Anat Rec. 2008;291:628–635
  123. Sherwood RI, Chen TY, Melton DA. Transcriptional dynamics of endodermal organ formation. Dev Dyn. 2009;238:29–42
  124. Sumazaki R, Shiojiri N, Isoyama S, et al. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet. 2004;36:83–87
  125. Fukuda A, Kawaguchi Y, Furuyama K, et al. Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas. J Clin Invest. 2006;116:1484–1493
  126. Fukuda A, Kawaguchi Y, Furuyama K, et al. Loss of the major duodenal papilla results in brown pigment biliary stone formation in pdx1 null mice. Gastroenterology. 2006;130:855–867
  127. Kalinichenko VV, Zhou Y, Bhattacharyya D, et al. Haploinsufficiency of the mouse Forkhead Box f1 gene causes defects in gall bladder development. J Biol Chem. 2002;277:12369–12374
  128. Tan CE, Moscoso GJ. The developing human biliary system at the porta hepatis level between 29 days and 8 weeks of gestation: a way to understanding biliary atresia. Part 1. Pathol Int. 1994;44:587–599
  129. Tan CE, Moscoso GJ. The developing human biliary system at the porta hepatis level between 11 and 25 weeks of gestation: a way to understanding biliary atresia. Part 2. Pathol Int. 1994;44:600–610
  130. Ito A, Nishikawa Y, Ohnuma K, et al. SgIGSF is a novel biliary-epithelial cell adhesion molecule mediating duct/ductule development. Hepatology. 2007;45:684–694
  131. Fabris L, Strazzabosco M, Crosby HA, et al. Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations. Am J Pathol. 2000;156:1599–1612
  132. Yamasaki H, Sada A, Iwata T, et al. Suppression of C/EBPα expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1β expression. Development. 2006;133:4233–4243
  133. Kodama Y, Hijikata M, Kageyama R, et al. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology. 2004;127:1775–1786
  134. Loomes KM, Russo P, Ryan M, et al. Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology. 2007;45:323–330
  135. Lorent K, Yeo SY, Oda T, et al. Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy. Development. 2004;131:5753–5766
  136. McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 2002;129:1075–1082
  137. Lozier J, McCright B, Gridley T. Notch signaling regulates bile duct morphogenesis in mice. PLoS One. 2008;3:e1851
  138. Geisler F, Nagl F, Mazur PK, et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 2008;48:607–616
  139. Suzuki K, Tanaka M, Watanabe N, et al. p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology. 2008;135:270–281
  140. Lemaigre FP. Notch signaling in bile duct development: new insights raise new questions. Hepatology. 2008;48:358–360
  141. Everson GT, Taylor MR, Doctor RB. Polycystic disease of the liver. Hepatology. 2004;40:774–782
  142. Johnson CA, Gissen P, Sergi C. Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet. 2003;40:311–319
  143. Kamath BM, Piccoli DA. Heritable disorders of the bile ducts. Gastroenterol Clin North Am. 2003;32:857–875
  144. Adams M, Smith UM, Logan CV, et al. Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J Med Genet. 2008;45:257–267
  145. Masyuk AI, Masyuk TV, LaRusso NF. Cholangiocyte primary cilia in liver health and disease. Dev Dyn. 2008;237:2007–2012
  146. Masyuk AI, Masyuk TV, Splinter PL, et al. Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology. 2006;131:911–920
  147. Gradilone SA, Masyuk AI, Splinter PL, et al. Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proc Natl Acad Sci U S A. 2007;104:19138–19143
  148. Masyuk AI, Gradilone SA, Banales JM, et al. Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am J Physiol Gastrointest Liver Physiol. 2008;295:G725–G734
  149. Bagnat M, Cheung ID, Mostov KE, et al. Genetic control of single lumen formation in the zebrafish gut. Nat Cell Biol. 2007;9:954–960
  150. Tanimizu N, Miyajima A, Mostov KE. Liver progenitor cells develop cholangiocyte-type epithelial polarity in three-dimensional culture. Mol Biol Cell. 2007;18:1472–1479
  151. Couvelard A, Bringuier AF, Dauge MC, et al. Expression of integrins during liver organogenesis in humans. Hepatology. 1998;27:839–847
  152. Fabris L, Cadamuro M, Fiorotto R, et al. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology. 2006;43:1001–1012
  153. Sato Y, Harada K, Kizawa K, et al. Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease. Am J Pathol. 2005;166:49–60
  154. Sato Y, Harada K, Furubo S, et al. Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib. Am J Pathol. 2006;169:1238–1250
  155. Lee SO, Masyuk T, Splinter P, et al. MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J Clin Invest. 2008;118:3714–3724
  156. Gissen P, Johnson CA, Morgan NV, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet. 2004;36:400–404
  157. Sadler KC, Amsterdam A, Soroka C, et al. A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease. Development. 2005;132:3561–3572
  158. Matthews RP, Plumb-Rudewiez N, Lorent K, et al. Zebrafish vps33b, an ortholog of the gene responsible for human arthrogryposis-renal dysfunction-cholestasis syndrome, regulates biliary development downstream of the onecut transcription factor hnf6. Development. 2005;132:5295–5306
  159. Clotman F, Libbrecht L, Killingsworth MC, et al. Lack of cilia and differentiation defects in the liver of human foetuses with the Meckel syndrome. Liver Int. 2008;28:377–384
  160. Strazzabosco M, Fabris L. Functional anatomy of normal bile ducts. Anat Rec. 2008;291:653–660
  161. Glaser S, Francis H, Demorrow S, et al. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol. 2006;12:3523–3536
  162. Collardeau-Frachon S, Scoazec JY. Vascular development and differentiation during human liver organogenesis. Anat Rec. 2008;291:614–627
  163. Geerts A. On the origin of stellate cells: mesodermal, endodermal or neuro-ectodermal?. J Hepatol. 2004;40:331–334
  164. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88:125–172
  165. Yang L, Jung Y, Omenetti A, et al. Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells. 2008;26:2104–2413

 Conflicts of interest The author discloses no conflicts.

 Funding Supported by the Interuniversity Attraction Poles Program (Belgian Science Policy), the D.G. Higher Education and Scientific Research of the French Community of Belgium, the Fund for Scientific Medical Research (Belgium), and the Alphonse & Jean Forton Fund.

PII: S0016-5085(09)00463-6

doi: 10.1053/j.gastro.2009.03.035

Gastroenterology
Volume 137, Issue 1 , Pages 62-79 , July 2009