The onecut transcription factor HNF6 is required for normal development of the biliary tract.

During liver development, hepatoblasts differentiate into hepatocytes or biliary epithelial cells (BEC). The BEC delineate the intrahepatic and extrahepatic bile ducts, and the gallbladder. The transcription factors that control the development of the biliary tract are unknown. Previous work has shown that the onecut transcription factor HNF6 is expressed in hepatoblasts and in the gallbladder primordium. We now show that HNF6 is also expressed in the BEC of the developing intrahepatic bile ducts, and investigate its involvement in biliary tract development by analyzing the phenotype of Hnf6(-/-) mice. In these mice, the gallbladder was absent, the extrahepatic bile ducts were abnormal and the development of the intrahepatic bile ducts was perturbed in the prenatal period. The morphology of the intrahepatic bile ducts was identical to that seen in mice whose Hnf1beta gene has been conditionally inactivated in the liver. HNF1beta expression was downregulated in the intrahepatic bile ducts of Hnf6(-/-) mice during development. Furthermore, we found that HNF6 can stimulate the Hnf1beta promoter. We conclude that HNF6 is essential for differentiation and morphogenesis of the biliary tract and that intrahepatic bile duct development is controlled by a HNF6-->HNF1beta cascade.

[1]  N. Shiojiri,et al.  Secondary joining of the bile ducts during the hepatogenesis of the mouse embryo , 2004, Anatomy and Embryology.

[2]  R. Sciot,et al.  Keratin immunohistochemistry in normal human liver. Cytokeratin pattern of hepatocytes, bile ducts and acinar gradient , 2004, Virchows Archiv A.

[3]  L. Gresh,et al.  Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. , 2002, Development.

[4]  T. Roskams,et al.  Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases , 2001, Histochemistry and Cell Biology.

[5]  Y. Sasakura,et al.  A gene encoding a new ONECUT class homeodomain protein in the ascidian Halocynthia roretzi functions in the differentiation and specification of neural cells in ascidian embryogenesis , 2001, Mechanisms of Development.

[6]  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.

[7]  S. Duncan.  Transcriptional regulation of liver development , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  Z. Lai,et al.  The Drosophila homolog of Onecut homeodomain proteins is a neural-specific transcriptional activator with a potential role in regulating neural differentiation , 2000, Mechanisms of Development.

[9]  M. Vekemans,et al.  JAGGED1 Gene Expression During Human Embryogenesis Elucidates the Wide Phenotypic Spectrum of Alagille Syndrome , 2000, Hepatology.

[10]  C. Bogue,et al.  Hex expression suggests a role in the development and function of organs derived from foregut endoderm , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  P. Carmeliet,et al.  Transcription Factor Hepatocyte Nuclear Factor 6 Regulates Pancreatic Endocrine Cell Differentiation and Controls Expression of the Proendocrine Gene ngn3 , 2000, Molecular and Cellular Biology.

[12]  J. Neuberger,et al.  Characterization and isolation of ductular cells coexpressing neural cell adhesion molecule and Bcl-2 from primary cholangiopathies and ductal plate malformations. , 2000, The American journal of pathology.

[13]  E. Fibach,et al.  Flow cytometric analysis of autonomous growth of erythroid precursors in liquid culture detects occult polycythemia vera in the Budd-Chiari syndrome. , 2000, Journal of hepatology.

[14]  K. Zaret,et al.  Liver specification and early morphogenesis , 2000, Mechanisms of Development.

[15]  G. Rousseau,et al.  Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone. , 2000, Molecular endocrinology.

[16]  G. Rousseau,et al.  CCAAT/enhancer-binding protein-alpha is a component of the growth hormone-regulated network of liver transcription factors. , 2000, Endocrinology.

[17]  G. Darlington.  Molecular mechanisms of liver development and differentiation. , 1999, Current opinion in cell biology.

[18]  M. Yaniv,et al.  Expression of the vHNF1/HNF1β homeoprotein gene during mouse organogenesis , 1999, Mechanisms of Development.

[19]  P. van Eyken,et al.  Hepatic jagged1 expression studies , 1999, Hepatology.

[20]  M. Yaniv,et al.  Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. , 1999, Development.

[21]  S. Cereghini,et al.  Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. , 1999, Development.

[22]  G. Rousseau,et al.  OC-2, a Novel Mammalian Member of the ONECUT Class of Homeodomain Transcription Factors Whose Function in Liver Partially Overlaps with That of Hepatocyte Nuclear Factor-6* , 1999, The Journal of Biological Chemistry.

[23]  J. Boyer,et al.  Molecular pathogenesis of cholestasis. , 2012, The New England journal of medicine.

[24]  F. Spagnoli,et al.  Identification of a Bipotential Precursor Cell in Hepatic Cell Lines Derived from Transgenic Mice Expressing Cyto-Met in the Liver , 1998, The Journal of cell biology.

[25]  K. Zaret,et al.  Early liver differentiation: genetic potentiation and multilevel growth control. , 1998, Current opinion in genetics & development.

[26]  G. Rousseau,et al.  Isoforms of Hepatocyte Nuclear Factor-6 Differ in DNA-binding Properties, Contain a Bifunctional Homeodomain, and Define the New ONECUT Class of Homeodomain Proteins* , 1998, The Journal of Biological Chemistry.

[27]  F. Suchy,et al.  The Intrahepatic Cholangiopathies , 1998, Seminars in liver disease.

[28]  C. Fletcher,et al.  The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas. , 1997, Developmental biology.

[29]  G. Rousseau,et al.  HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. , 1997, Developmental biology.

[30]  N. Shiojiri.  Development and differentiation of bile ducts in the mammalian liver , 1997, Microscopy research and technique.

[31]  N. Shiojiri,et al.  Differentiation of biliary epithelial cells from the mouse hepatic endodermal cells cultured in vitro. , 1997, The Tohoku journal of experimental medicine.

[32]  J. Hsuan,et al.  Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Michalopoulos,et al.  Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium , 1996, The Journal of cell biology.

[34]  S. Cereghini,et al.  Positive regulation of the vHNF1 promoter by the orphan receptors COUP-TF1/Ear3 and COUP-TFII/Arp1 , 1996, Molecular and cellular biology.

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

[36]  T. Sanzen.  P-406 Cell proliferation and apoptosis of intra-hepatic bile duct of rats during its development and maturation , 1995 .

[37]  T. Terada,et al.  Detection of apoptosis and expression of apoptosis-related proteins during human intrahepatic bile duct development. , 1995, The American journal of pathology.

[38]  T. Terada,et al.  Expression of tenascin, type IV collagen and laminin during human intrahepatic bile duct development and in intrahepatic cholangiocarcinoma , 1994, Histopathology.

[39]  K. Matsumoto,et al.  Hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells , 1993, Hepatology.

[40]  G. Weinmaster,et al.  Notch2: a second mammalian Notch gene. , 1992, Development.

[41]  S. Cereghini,et al.  Expression patterns of vHNF1 and HNF1 homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles. , 1992, Development.

[42]  V. Desmet.  Congenital diseases of intrahepatic bile ducts: Variations on the theme “ductal plate malformation” , 1992, Hepatology.

[43]  Matthew H. Kaufman,et al.  The Atlas of Mouse Development , 1992 .

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

[45]  Shah Kd,et al.  Development of intrahepatic bile ducts in humans. Possible role of laminin. , 1990 .

[46]  M. Gerber,et al.  Development of intrahepatic bile ducts in humans. Possible role of laminin. , 1990, Archives of pathology & laboratory medicine.

[47]  P. van Eyken,et al.  The development of the intrahepatic bile ducts in man: A keratin‐immunohistochemical study , 1988, Hepatology.

[48]  N. Marceau,et al.  Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, albumin, and cell surface-exposed components. , 1988, Cancer Research.

[49]  P. van Eyken,et al.  Intrahepatic bile duct development in the rat: a cytokeratin-immunohistochemical study. , 1988, Laboratory investigation; a journal of technical methods and pathology.

[50]  N. Shiojiri.  The origin of intrahepatic bile duct cells in the mouse. , 1984, Journal of embryology and experimental morphology.