The Fox genes in the liver: from organogenesis to functional integration.

Formation and function of the liver are highly controlled, essential processes. Multiple signaling pathways and transcriptional regulatory networks cooperate in this complex system. The evolutionarily conserved FOX, for Forkhead bOX, class of transcriptional regulators is critical to many aspects of liver development and function. The FOX proteins are small, mostly monomeric DNA binding factors containing the so-called winged helix DNA binding motif that distinguishes them from other classes of transcription factors. We discuss the biochemical and genetic roles of Foxa, Foxl1, Foxm1, and Foxo, as these have been shown to regulate many processes throughout the life of the organ, controlling both formation and function of the liver.

[1]  B. Spear,et al.  The mouse alpha-fetoprotein promoter is repressed in HepG2 hepatoma cells by hepatocyte nuclear factor-3 (FOXA). , 2002, DNA and cell biology.

[2]  J. Darnell,et al.  Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells. , 1991, The New biologist.

[3]  S. Burley,et al.  Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5 , 1993, Nature.

[4]  N. Shiojiri.  Analysis of Differentiation of Hepatocytes and Bile Duct Cells in Developing Mouse Liver by Albumin Immunofluorescence , 1984, Development, growth & differentiation.

[5]  K. Zaret,et al.  Initiation of mammalian liver development from endoderm by fibroblast growth factors. , 1999, Science.

[6]  P. Cohen,et al.  Phosphorylation of the Transcription Factor Forkhead Family Member FKHR by Protein Kinase B* , 1999, The Journal of Biological Chemistry.

[7]  Franghiz Ali-Zadeh,et al.  In search of , 2005 .

[8]  B. Hogan,et al.  Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. , 2001, Genes & development.

[9]  K. Arden.  FoxO: linking new signaling pathways. , 2004, Molecular cell.

[10]  Jian Xu,et al.  Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm. , 2008, Cold Spring Harbor symposia on quantitative biology.

[11]  R. O’Brien,et al.  Regulation of Phosphoenolpyruvate Carboxykinase and Insulin-like Growth Factor-binding Protein-1 Gene Expression by Insulin , 2000, The Journal of Biological Chemistry.

[12]  K. Kaestner,et al.  Mild Nephrogenic Diabetes Insipidus Caused by Foxa1 Deficiency* , 2004, Journal of Biological Chemistry.

[13]  W. Biggs,et al.  Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Hofmann,et al.  Bile Acids: The Good, the Bad, and the Ugly. , 1999, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[15]  E. Lai,et al.  Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Burgess,et al.  Diminished Hepatic Gluconeogenesis via Defects in Tricarboxylic Acid Cycle Flux in Peroxisome Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)-deficient Mice* , 2006, Journal of Biological Chemistry.

[17]  D Weigel,et al.  The fork head domain: A novel DNA binding motif of eukaryotic transcription factors? , 1990, Cell.

[18]  D. Accili,et al.  Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1 , 2002, Nature Genetics.

[19]  S. Peng,et al.  Foxo in the immune system , 2008, Oncogene.

[20]  Jonathan P. Katz,et al.  Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo. , 1999, Genes & development.

[21]  M. Stoffel,et al.  Profound defects in pancreatic beta-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1alpha, and Hnf-3beta. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  K. Kaestner,et al.  Foxa2 controls Pdx1 gene expression in pancreatic beta-cells in vivo. , 2002, Diabetes.

[23]  R. Jordan,et al.  Molecular viral oncology of hepatocellular carcinoma , 2003, Oncogene.

[24]  K. Kaestner,et al.  Stage-specific regulation of respiratory epithelial cell differentiation by Foxa1. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[25]  Christian Wolfrum,et al.  Role of Foxa-2 in adipocyte metabolism and differentiation. , 2003, The Journal of clinical investigation.

[26]  M. Birnbaum,et al.  Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator , 2007, Nature.

[27]  Simon C Watkins,et al.  Elevated Levels of Hepatocyte Nuclear Factor 3β in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis , 2000, Molecular and Cellular Biology.

[28]  Phillip P. Le,et al.  Impaired male fertility and atrophy of seminiferous tubules caused by haploinsufficiency for Foxa3. , 2007, Developmental biology.

[29]  M. Birnbaum,et al.  The role of FoxO in the regulation of metabolism , 2008, Oncogene.

[30]  Xueying Lin,et al.  Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. , 2006, The Journal of clinical investigation.

[31]  D. Accili,et al.  The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. , 2001, The Journal of clinical investigation.

[32]  J. Wells,et al.  Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung , 2004, Development.

[33]  S. Thorgeirsson,et al.  Proliferation, apoptosis, and induction of hepatic transcription factors are characteristics of the early response of biliary epithelial (oval) cells to chemical carcinogens , 1996, Hepatology.

[34]  Bruce M. Spiegelman,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction , 2003, Nature.

[35]  J. Philippe.  Hepatocyte-nuclear factor 3 beta gene transcripts generate protein isoforms with different transactivation properties on the glucagon gene. , 1995, Molecular endocrinology.

[36]  N. Fausto.  Liver regeneration and repair: Hepatocytes, progenitor cells, and stem cells , 2004, Hepatology.

[37]  M. Barton,et al.  Hepatocyte nuclear factor 3 relieves chromatin-mediated repression of the alpha-fetoprotein gene. , 1999, The Journal of biological chemistry.

[38]  M. Katoh,et al.  Human FOX gene family (Review). , 2004, International journal of oncology.

[39]  D. Gerber,et al.  Hepatic Stem Cells: In Search of , 2006, Stem cells.

[40]  P. Lucas,et al.  Hormone response domains in gene transcription. , 1992, Annual review of biochemistry.

[41]  K. Kaestner,et al.  An FGF response pathway that mediates hepatic gene induction in embryonic endoderm cells. , 2006, Developmental cell.

[42]  J. Philippe,et al.  Glucagon gene expression is negatively regulated by hepatocyte nuclear factor 3 beta , 1994, Molecular and cellular biology.

[43]  K. Zaret,et al.  Regulatory phases of early liver development: paradigms of organogenesis , 2002, Nature Reviews Genetics.

[44]  K. Kaestner.  The making of the liver: developmental competence in foregut endoderm and induction of the hepatogenic program. , 2005, Cell cycle.

[45]  J. Wang,et al.  Hepatic nuclear factor 3 is an accessory factor required for the stimulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. , 1996, Molecular endocrinology.

[46]  Klaus H. Kaestner,et al.  The HNF-3 gene family of transcription factors in mice: gene structure, cDNA sequence, and mRNA distribution. , 1994, Genomics.

[47]  P. van Eyken,et al.  Ductular reaction in the liver. , 1995, Pathology, research and practice.

[48]  D. Accili,et al.  FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation , 2004, Cell.

[49]  J. Locker,et al.  Characterization of the distal alpha-fetoprotein enhancer, a strong, long distance, liver-specific activator. , 1994, The Journal of biological chemistry.

[50]  J. Darnell,et al.  A liver-specific DNA-binding protein recognizes multiple nucleotide sites in regulatory regions of transthyretin, alpha 1-antitrypsin, albumin, and simian virus 40 genes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[51]  M. White,et al.  The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. , 2006, Molecular endocrinology.

[52]  S. Duncan,et al.  Embryonic development of the liver , 2005, Hepatology.

[53]  A. Datta,et al.  Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. , 2004, Genes & development.

[54]  J. Cha,et al.  HNF1 and/or HNF3 may contribute to the tissue specific expression of glucokinase gene , 2001, Experimental & Molecular Medicine.

[55]  Thomas M. Jessell,et al.  The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo , 1994, Cell.

[56]  S. Sell,et al.  Liver cancer stem cells. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  R. O’Brien,et al.  Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. , 1999, Diabetes.

[58]  R. Walther,et al.  Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. , 2000, The Journal of biological chemistry.

[59]  K. Kaestner,et al.  Foxa2 is required for the differentiation of pancreatic alpha-cells. , 2005, Developmental biology.

[60]  G. Tuteja,et al.  SnapShot:Forkhead Transcription Factors I , 2007, Cell.

[61]  Richard W. Hanson,et al.  Factors That Control the Tissue-Specific Transcription of the Gene for Phosphoenolpyruvate Carboxykinase-C , 2005, Critical reviews in biochemistry and molecular biology.

[62]  K. Zaret,et al.  An early developmental transcription factor complex that is more stable on nucleosome core particles than on free DNA. , 1999, Molecular cell.

[63]  G. Michalopoulos,et al.  Liver Regeneration , 1997, Science.

[64]  K. Zaret,et al.  Repressive and restrictive mesodermal interactions with gut endoderm: possible relation to Meckel's Diverticulum. , 2000, Development.

[65]  J. Wang,et al.  Structural requirements of the glucocorticoid and retinoic acid response units in the phosphoenolpyruvate carboxykinase gene promoter. , 1998, Molecular endocrinology.

[66]  T. Yatskievych,et al.  Regulation of Hex gene expression and initial stages of avian hepatogenesis by Bmp and Fgf signaling. , 2004, Developmental biology.

[67]  R A Roth,et al.  Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. , 2001, Biochemical and biophysical research communications.

[68]  M. Barton,et al.  Hepatocyte Nuclear Factor 3 Relieves Chromatin-mediated Repression of the α-Fetoprotein Gene* , 1999, The Journal of Biological Chemistry.

[69]  C. Kahn,et al.  Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. , 2000, Molecular cell.

[70]  G. Ruvkun,et al.  The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans , 1997, Nature.

[71]  N. L. Le Douarin.  [Role of mesenchyme in hepatic histogenesis in the chick embryo]. , 1963, Comptes rendus hebdomadaires des seances de l'Academie des sciences.

[72]  K. Kaestner,et al.  Foxa2 is required for the differentiation of pancreatic α-cells , 2005 .

[73]  E. Cerasi,et al.  A pancreatic beta -cell-specific enhancer in the human PDX-1 gene is regulated by hepatocyte nuclear factor 3beta (HNF-3beta ), HNF-1alpha, and SPs transcription factors. , 2001, The Journal of biological chemistry.

[74]  P De Meyts,et al.  Inhibition by insulin of glucocorticoid-induced gene transcription: involvement of the ligand-binding domain of the glucocorticoid receptor and independence from the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. , 1998, Molecular endocrinology.

[75]  R. Costa,et al.  Transplanted hepatocytes over-expressing FoxM1B efficiently repopulate chronically injured mouse liver independent of donor age. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[76]  Michael Courtois,et al.  PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis , 2005, PLoS Biology.

[77]  J. Darnell,et al.  Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. , 1991, Genes & development.

[78]  A. Moschetta.  Welcoming Foxa2 in the bile acid entourage. , 2008, Cell metabolism.

[79]  S. Burgess,et al.  Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-deficient mice. , 2006, The Journal of biological chemistry.

[80]  K. Kaestner,et al.  Foxa3 (Hepatocyte Nuclear Factor 3γ) Is Required for the Regulation of Hepatic GLUT2 Expression and the Maintenance of Glucose Homeostasis during a Prolonged Fast* , 2001, The Journal of Biological Chemistry.

[81]  R. Costa,et al.  Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[82]  R. Arakaki,et al.  Distribution pattern of HNF‐3β proteins in developing embryos of two mammalian species, the house shrew and the mouse , 1997, Development, growth & differentiation.

[83]  M. Grompe.  The origin of hepatocytes. , 2005, Gastroenterology.

[84]  M. Stoffel,et al.  Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1α, and Hnf-3β , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[85]  R. Walther,et al.  Characterization of cis-elements mediating the stimulation of glucose-6-phosphate transporter promoter activity by glucocorticoids. , 2003, Gene.

[86]  S. Kliewer,et al.  Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. , 2005, Cell metabolism.

[87]  R. L. Wood.  Regeneration of Liver and Kidney , 1971 .

[88]  M. Grompe,et al.  Liver repair by intra- and extrahepatic progenitors , 2007, Stem Cell Reviews.

[89]  A. Kahn,et al.  Overproduction of a truncated hepatocyte nuclear factor 3 protein inhibits expression of liver-specific genes in hepatoma cells , 1995, Molecular and cellular biology.

[90]  Y. Dragan,et al.  Karyotypic changes in a multistage model of chemical hepatocarcinogenesis in the rat. , 1996, Cancer research.

[91]  T. Hayamizu,et al.  Transcription Factor FoxA (HNF3) on a Nucleosome at an Enhancer Complex in Liver Chromatin* , 2001, The Journal of Biological Chemistry.

[92]  A. Fukamizu,et al.  Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. , 2003, Diabetes.

[93]  P. Cohen,et al.  Phosphorylation of Serine 256 by Protein Kinase B Disrupts Transactivation by FKHR and Mediates Effects of Insulin on Insulin-like Growth Factor-binding Protein-1 Promoter Activity through a Conserved Insulin Response Sequence* , 1999, The Journal of Biological Chemistry.

[94]  K. Kaestner,et al.  The Hepatocyte Nuclear Factor 3 (HNF3 or FOXA) Family in Metabolism , 2000, Trends in Endocrinology & Metabolism.

[95]  J. Darnell,et al.  Sequential expression of HNF-3 beta and HNF-3 alpha by embryonic organizing centers: the dorsal lip/node, notochord and floor plate. , 1993, Mechanisms of development.

[96]  Y. Kido,et al.  The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. , 2002, The Journal of clinical investigation.

[97]  J. Lemire,et al.  Cell lineages and oval cell progenitors in rat liver development. , 1991, Cancer research.

[98]  R. DePinho,et al.  Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. , 2007, Cell metabolism.

[99]  R. Chalkley,et al.  Interaction of a liver-specific factor with an enhancer 4.8 kilobases upstream of the phosphoenolpyruvate carboxykinase gene , 1990, Molecular and cellular biology.

[100]  S. Monga,et al.  Wnt/β-catenin signaling in hepatic organogenesis , 2008 .

[101]  J. Rossant,et al.  HNF-3 beta is essential for node and notochord formation in mouse development. , 1994, Cell.

[102]  J. Darnell,et al.  HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. , 1990, Genes & development.

[103]  Jiandie D. Lin,et al.  Defects in Adaptive Energy Metabolism with CNS-Linked Hyperactivity in PGC-1α Null Mice , 2004, Cell.

[104]  J. Darnell,et al.  Hepatocyte nuclear factor 3/fork head or "winged helix" proteins: a family of transcription factors of diverse biologic function. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[105]  T. Furuyama,et al.  Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. , 2003, The Biochemical journal.

[106]  J. Beechem,et al.  Accessory Factors Facilitate the Binding of Glucocorticoid Receptor to the Phosphoenolpyruvate Carboxykinase Gene Promoter* , 2001, The Journal of Biological Chemistry.

[107]  J. Wang,et al.  Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes , 1995, Molecular and cellular biology.

[108]  Klaus H. Kaestner,et al.  Targeted Disruption of the Gene Encoding Hepatocyte Nuclear Factor 3γ Results in Reduced Transcription of Hepatocyte-Specific Genes , 1998, Molecular and Cellular Biology.

[109]  C. Kahn,et al.  Critical nodes in signalling pathways: insights into insulin action , 2006, Nature Reviews Molecular Cell Biology.

[110]  K. Zaret,et al.  A bipotential precursor population for pancreas and liver within the embryonic endoderm. , 2001, Development.

[111]  Klaus H. Kaestner,et al.  The initiation of liver development is dependent on Foxa transcription factors , 2005, Nature.

[112]  J. R. Coleman,et al.  Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. , 1996, Genes & development.

[113]  J. Grisham,et al.  A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. , 1962, Cancer research.

[114]  K. Kaestner,et al.  Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. , 1993, Development.

[115]  M. Stoffel,et al.  Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes , 2004, Nature.

[116]  Y. Patel,et al.  Metabolic control of gene expression: in vivo studies with transgenic mice. , 1992, Trends in biochemical sciences.

[117]  K. Zaret,et al.  Developmental competence of the gut endoderm: genetic potentiation by GATA and HNF3/fork head proteins. , 1999, Developmental biology.

[118]  M. Stoffel,et al.  Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[119]  B. Hogan,et al.  Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. , 1993, Development.

[120]  E. Houssaint,et al.  [Role of the mesoderm in the induction of the synthesis of glycogen during differentiation of the hepatic endoderm]. , 1967, Comptes rendus hebdomadaires des seances de l'Academie des sciences. Serie D: Sciences naturelles.

[121]  P. Meier,et al.  Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[122]  J. Mirosevich,et al.  Expression of Foxa transcription factors in the developing and adult murine prostate , 2005, The Prostate.

[123]  R. Stein,et al.  Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene , 1997, Molecular and cellular biology.

[124]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[125]  Kazuya Yamada,et al.  Transducin-like Enhancer of Split Proteins, the Human Homologs of Drosophila Groucho, Interact with Hepatic Nuclear Factor 3β* , 2000, The Journal of Biological Chemistry.

[126]  E. Scott,et al.  Mouse A6–positive hepatic oval cells also express several hematopoietic stem cell markers , 2003, Hepatology.

[127]  R. Pictet,et al.  Glucocorticoids are insufficient for neonatal gene induction in the liver. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[128]  土田 敦之.  Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity , 2005 .

[129]  D. Powell,et al.  Glucocorticoids and insulin regulate expression of the human gene for insulin-like growth factor-binding protein-1 through proximal promoter elements. , 1994, The Journal of biological chemistry.

[130]  K. Kaestner,et al.  Foxl1 is a marker of bipotential hepatic progenitor cells in mice , 2009, Hepatology.

[131]  K. Zaret,et al.  An active tissue-specific enhancer and bound transcription factors existing in a precisely positioned nucleosomal array , 1993, Cell.

[132]  B. Hogan,et al.  Enhancer analysis of the mouse HNF‐3β gene: regulatory elements for node/notochord and floor plate are independent and consist of multiple sub‐ elements , 1996, Genes to cells : devoted to molecular & cellular mechanisms.

[133]  K. Kaestner,et al.  Foxa2 integrates the transcriptional response of the hepatocyte to fasting. , 2005, Cell metabolism.

[134]  T. Unterman,et al.  FoxO proteins in insulin action and metabolism , 2005, Trends in Endocrinology & Metabolism.

[135]  K. Kaestner.  Fox genes in glucose homeostasis , 2003 .

[136]  A. I. Goussev,et al.  Ultrastructural localisation of alpha-fetoprotin (AFP) in regenerating mouse liver poisoned with CCL4 , 1984, Histochemistry.

[137]  J. Ward,et al.  Rapid development of hepatic tumors in transforming growth factor alpha transgenic mice associated with increased cell proliferation in precancerous hepatocellular lesions initiated by N-nitrosodiethylamine and promoted by phenobarbital. , 1994, Carcinogenesis.

[138]  V. Ramakrishnan,et al.  Crystal structure of globular domain of histone H5 and its implications for nucleosome binding , 1993, Nature.

[139]  K. Kaestner,et al.  The Foxa family of transcription factors in development and metabolism , 2006, Cellular and Molecular Life Sciences CMLS.

[140]  G. Schütz,et al.  Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcriptional activators. , 1993, Genes & development.

[141]  G. Michalopoulos,et al.  Hepatic oval cells express the hematopoietic stem cell marker thy‐1 in the rat , 1998, Hepatology.

[142]  Erol Cerasi,et al.  A Pancreatic β-Cell-specific Enhancer in the HumanPDX-1 Gene Is Regulated by Hepatocyte Nuclear Factor 3β (HNF-3β), HNF-1α, and SPs Transcription Factors* , 2001, The Journal of Biological Chemistry.

[143]  M. Manns,et al.  Stem cells in liver regeneration and therapy , 2007, Cell and Tissue Research.

[144]  R. Costa,et al.  Transcription factors in liver development, differentiation, and regeneration , 2003, Hepatology.

[145]  D. Haro,et al.  Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1. , 2002, The Biochemical journal.

[146]  Reiichiro Kuwahara,et al.  The Hepatic Stem Cell Niche: Identification by Label-retaining Cell Assay Tion. Currently, State-of-the-art Experimental Approaches , 2007 .

[147]  G. Schütz,et al.  Activation of the tyrosine aminotransferase gene is dependent on synergy between liver-specific and hormone-responsive elements. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[148]  F. Sladek,et al.  The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[149]  M. Golding,et al.  Liver stem cells: when the going gets tough they get going , 1997, International journal of experimental pathology.

[150]  K. Kaestner,et al.  Foxa2 Controls Pdx1 Gene Expression in Pancreatic β-Cells In Vivo , 2002 .

[151]  Lee Cs,et al.  Histochemical studies of mouse liver after single feeding of carbon tetrachloride. , 1950 .

[152]  Frank R. Lin,et al.  Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. , 2002, Molecular cell.

[153]  Robert Tjian,et al.  Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. , 2005, Genes & development.

[154]  A. Zorn,et al.  Repression of Wnt/β-catenin signaling in the anterior endoderm is essential for liver and pancreas development , 2007, Development.

[155]  J. Wang,et al.  The phosphoenolpyruvate carboxykinase gene glucocorticoid response unit: identification of the functional domains of accessory factors HNF3 beta (hepatic nuclear factor-3 beta) and HNF4 and the necessity of proper alignment of their cognate binding sites. , 1999, Molecular endocrinology.

[156]  B. Cieply,et al.  Wnt/β‐catenin signaling mediates oval cell response in rodents , 2007 .

[157]  M. Magnuson,et al.  Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. , 2007, Cell metabolism.

[158]  K. Zaret,et al.  GATA transcription factors as potentiators of gut endoderm differentiation. , 1998, Development.

[159]  C. Wollheim,et al.  Does chasing selected 'Fox' to the nucleus prevent diabetes? , 2005, Trends in molecular medicine.

[160]  Jiandie D. Lin,et al.  Nutritional Regulation of Hepatic Heme Biosynthesis and Porphyria through PGC-1α , 2005, Cell.

[161]  G. Alpini,et al.  Fate‐Mapping Evidence That Hepatic Stellate Cells Are Epithelial Progenitors in Adult Mouse Livers , 2008, Stem cells.

[162]  R. Pictet,et al.  Hepatocyte nuclear factor 3 determines the amplitude of the glucocorticoid response of the rat tyrosine aminotransferase gene. , 1995, DNA and cell biology.

[163]  S. Orkin,et al.  CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[164]  K. Zaret.  Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation , 2008, Nature Reviews Genetics.

[165]  K. Arden.  FOXO animal models reveal a variety of diverse roles for FOXO transcription factors , 2008, Oncogene.

[166]  T. Unterman,et al.  Hepatocyte nuclear factor-3 (HNF-3) binds to the insulin response sequence in the IGF binding protein-1 (IGFBP-1) promoter and enhances promoter function. , 1994, Biochemical and biophysical research communications.

[167]  Johan Auwerx,et al.  Targeting bile-acid signalling for metabolic diseases , 2008, Nature Reviews Drug Discovery.

[168]  K. Kaestner,et al.  Winged-helix transcription factors and pancreatic development. , 2005, Clinical science.

[169]  Robert A. Harris,et al.  Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. , 2004, Diabetes.

[170]  R. Chalkley,et al.  Phosphoenolpyruvate Carboxykinase Is Necessary for the Integration of Hepatic Energy Metabolism , 2000, Molecular and Cellular Biology.

[171]  Jerry Donovan,et al.  Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. , 2003, Nature.

[172]  J. Rossant,et al.  The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. , 1993, Development.

[173]  H. Deng,et al.  Failure of hepatocyte marker-expressing hematopoietic progenitor cells to efficiently convert into hepatocytes in vitro. , 2006, Experimental hematology.

[174]  J E Darnell,et al.  Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes , 1989, Molecular and cellular biology.

[175]  T. Hunter,et al.  Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[176]  J. Darnell,et al.  Sequential expression of HNF-3β and HNF-3α by embryonic organizing centers: the dorsal lip/node, notochord and floor plate , 1993, Mechanisms of Development.

[177]  M. Grompe,et al.  Generation and Regeneration of Cells of the Liver and Pancreas , 2008, Science.

[178]  D. Riddle,et al.  Interacting genes in nematode dauer larva formation , 1981, Nature.

[179]  S. Kalinin,et al.  Sustained hepatic expression of FoxM1B in transgenic mice has minimal effects on hepatocellular carcinoma development but increases cell proliferation rates in preneoplastic and early neoplastic lesions , 2003, Oncogene.

[180]  R. O’Brien,et al.  Integration of multiple signals through a complex hormone response unit in the phosphoenolpyruvate carboxykinase gene promoter. , 1994, Molecular endocrinology.

[181]  B. Cieply,et al.  β‐Catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development , 2008, Hepatology.

[182]  Peter White,et al.  Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress , 2008, Nature Medicine.

[183]  D. Stainier,et al.  Bmp and Fgf signaling are essential for liver specification in zebrafish , 2007, Development.

[184]  M. Strazzabosco.  Foxa1 and Foxa2 regulate bile duct development in mice. , 2010, Journal of hepatology.

[185]  K. Zaret,et al.  Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. , 2005, Developmental biology.

[186]  J. W. Steiner,et al.  Cell population dynamics in the liver. A review of quantitative morphological techniques applied to the study of physiological and pathological growth. , 1966, Experimental and molecular pathology.

[187]  B. Cieply,et al.  Wnt/beta-catenin signaling mediates oval cell response in rodents. , 2008, Hepatology.

[188]  J. Rossant,et al.  HNF-3β is essential for node and notochord formation in mouse development , 1994, Cell.

[189]  R. Costa,et al.  Hepatocyte nuclear factor-3 alpha promoter regulation involves recognition by cell-specific factors, thyroid transcription factor-1, and autoactivation. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[190]  D. Stainier,et al.  Mesodermal Wnt2b signalling positively regulates liver specification , 2006, Nature.

[191]  T. Unterman,et al.  Gene- and Activation-specific Mechanisms for Insulin Inhibition of Basal and Glucocorticoid-induced Insulin-like Growth Factor Binding Protein-1 and Phosphoenolpyruvate Carboxykinase Transcription , 2001, The Journal of Biological Chemistry.

[192]  M. Grompe,et al.  Surface markers for the murine oval cell response , 2008, Hepatology.

[193]  S. Fukuda-Taira.  Hepatic induction in the avian embryo: specificity of reactive endoderm and inductive mesoderm. , 1981, Journal of embryology and experimental morphology.

[194]  Falk Weih,et al.  The cyclic adenosine 3',5'-monophosphate- and the glucocorticoid-dependent enhancers are targets for insulin repression of tyrosine aminotransferase gene transcription. , 1994, Molecular endocrinology.

[195]  K. Kaestner,et al.  Six members of the mouse forkhead gene family are developmentally regulated. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[196]  I. Weissman,et al.  Pioneer factor interactions and unmethylated CpG dinucleotides mark silent tissue-specific enhancers in embryonic stem cells , 2007, Proceedings of the National Academy of Sciences.

[197]  K. Kaestner,et al.  Foxa2 regulates multiple pathways of insulin secretion. , 2004, The Journal of clinical investigation.

[198]  Marc Montminy,et al.  CREB regulates hepatic gluconeogenesis through the coactivator PGC-1 , 2001, Nature.

[199]  George K Michalopoulos,et al.  Liver regeneration. , 2005, Advances in biochemical engineering/biotechnology.

[200]  R. Anderson,et al.  Experimental pathology of liver: restoration of liver in white rat following partial surgical removal , 1931 .

[201]  S. Cereghini.  Liver‐enriched transcription factors and hepatocyte differentiation , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[202]  S. Tilghman,et al.  Molecular analysis of the distal enhancer of the mouse alpha-fetoprotein gene , 1995, Molecular and cellular biology.

[203]  S. Sell.  The role of progenitor cells in repair of liver injury and in liver transplantation , 2001, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[204]  Haiyan Wang,et al.  Foxa2 (HNF3β) Controls Multiple Genes Implicated in Metabolism-Secretion Coupling of Glucose-induced Insulin Release* , 2002, The Journal of Biological Chemistry.

[205]  N. Ledouarin.  Role of mesenchyme in hepatic histogenesis in the chick embryo , 1963 .

[206]  S. Monga,et al.  Wnt/beta-catenin signaling in hepatic organogenesis. , 2008, Organogenesis.

[207]  K. Zaret,et al.  Molecular genetics of early liver development. , 1996, Annual review of physiology.

[208]  A. Fukamizu,et al.  Foxo1 links insulin signaling to C/EBPα and regulates gluconeogenesis during liver development , 2007, The EMBO journal.

[209]  T. Pieler,et al.  Cell-autonomous and signal-dependent expression of liver and intestine marker genes in pluripotent precursor cells from Xenopus embryos , 2003, Mechanisms of Development.

[210]  H. Jäckle,et al.  The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo , 1989, Cell.

[211]  D. Powell,et al.  Hepatic nuclear factor 3 and high mobility group I/Y proteins bind the insulin response element of the insulin-like growth factor-binding protein-1 promoter. , 1997, Endocrinology.

[212]  J. Cha,et al.  Identification of Transacting Factors Responsible for the Tissue-specific Expression of Human Glucose Transporter Type 2 Isoform Gene , 2000, The Journal of Biological Chemistry.

[213]  R. Pictet,et al.  In vivo footprinting of rat TAT gene: Dynamic interplay between the glucocorticoid receptor and a liver-specific factor , 1991, Cell.

[214]  J. Bruix,et al.  Treatment of hepatocellular carcinoma: is there an optimal strategy? , 2003, Cancer treatment reviews.

[215]  W. V. Berghe,et al.  Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[216]  R. Costa,et al.  New and unexpected: forkhead meets ARF. , 2005, Current opinion in genetics & development.

[217]  S. Thorgeirsson.  Hepatic stem cells in liver regeneration , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[218]  W. Knöchel,et al.  Of Fox and Frogs: Fox (fork head/winged helix) transcription factors in Xenopus development. , 2005, Gene.

[219]  N. Daigle,et al.  Hepatocyte Nuclear Factor 3β (Foxa2) Is Dispensable for Maintaining the Differentiated State of the Adult Hepatocyte , 2000, Molecular and Cellular Biology.

[220]  P. Wijchers,et al.  In control of biology: of mice, men and Foxes. , 2006, The Biochemical journal.

[221]  Yonghong Xiao,et al.  FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis , 2007, Cell.

[222]  Kang-Yun Lee,et al.  Glucocorticoid suppression of CX3CL1 (fractalkine) by reduced gene promoter recruitment of NF‐κB , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.