Characterization of the mouse HNF-4 gene and its expression during mouse embryogenesis

Hepatocyte nuclear factor 4 (HNF-4) is a member of the nuclear receptor gene superfamily with unknown ligand. It has been assumed to play an important role in the regulation of gene expression in the liver. Here, we report the cloning and characterization of the mouse HNF-4 gene, as well as its expression during embryogenesis. The HNF-4 protein is encoded by ten exons. The gene structure is unique in the steroid receptor superfamily in that the second zinc finger is encoded by two exons. HNF-4 mRNA is expressed in a limited number of mouse adult tissues: liver, kidney, intestine, stomach and skin. HNF-4 could play an important role in the formation and function of visceral yolk sac and in the development of the liver and kidney since its mRNA, as determined by in situ hybridization, appears upon primary differentiation of these organs. As a first step in the study of the regulatory elements of the HNF-4 gene, we mapped the transcription start site and carried out DNase I hypersensitive site (HS) analysis over a region of approximately 22kb upstream of the gene. The complexity of the HSs suggests that multiple elements might contribute to the transcriptional regulation of the HNF-4 gene.

[1]  M. Moisan,et al.  Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. , 1993, Molecular endocrinology.

[2]  David Housman,et al.  WT-1 is required for early kidney development , 1993, Cell.

[3]  V. Laudet,et al.  Genomic organization of the human thyroid hormone receptor α (c-erbA-1) gene , 1991 .

[4]  C. DiPersio,et al.  Extracellular signals that regulate liver transcription factors during hepatic differentiation in vitro , 1991, Molecular and cellular biology.

[5]  G. Adelmant,et al.  Characterization of a functional promoter for the human thyroid hormone receptor alpha (c-erbA-1) gene. , 1993, Oncogene.

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

[7]  S. Karathanasis,et al.  Repression by ARP-1 sensitizes apolipoprotein AI gene responsiveness to RXR alpha and retinoic acid , 1992, Molecular and cellular biology.

[8]  Gerhard Giebisch,et al.  The Kidney: Physiology and Pathophysiology , 1992 .

[9]  M. Blumenfeld,et al.  Hepatic nuclear factor 1 (HNF1) shows a wider distribution than products of its known target genes in developing mouse. , 1991, Development.

[10]  P. Angrand,et al.  HNF4 and HNF1 as well as a panel of hepatic functions are extinguished and reexpressed in parallel in chromosomally reduced rat hepatoma-human fibroblast hybrids , 1993, The Journal of cell biology.

[11]  D. Hogness,et al.  The E75 ecdysone-inducible gene responsible for the 75B early puff in Drosophila encodes two new members of the steroid receptor superfamily. , 1990, Genes & development.

[12]  W. Schulz,et al.  Coexpression of the C-MYC protooncogene with α-fetoprotein and albumin in fetal mouse liver , 1990 .

[13]  R. Pedersen,et al.  Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. , 1991, Development.

[14]  J. Darnell,et al.  Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. , 1990, Genes & development.

[15]  G. Crabtree,et al.  A transcriptional hierarchy involved in mammalian cell-type specification , 1992, Nature.

[16]  T. Tsukamoto,et al.  A novel isoform of rat hepatocyte nuclear factor 4 (HNF-4). , 1992, Biochimica et biophysica acta.

[17]  K. Kaestner,et al.  Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase. , 1989, The Journal of biological chemistry.

[18]  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.

[19]  S. Araki,et al.  Prealbumin gene expression during mouse development studied by in situ hybridization. , 1987, Cell differentiation.

[20]  A. Feinberg,et al.  A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. , 1983, Analytical biochemistry.

[21]  W. Guder,et al.  Enzyme distribution along the nephron. , 1984, Kidney international.

[22]  D. Moore,et al.  Hepatocyte nuclear factor-4 activates medium chain acyl-CoA dehydrogenase gene transcription by interacting with a complex regulatory element. , 1993, The Journal of biological chemistry.

[23]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[24]  E. Linney,et al.  The mouse retinoid-X receptor-gamma gene: genomic organization and evidence for functional isoforms. , 1993, Molecular endocrinology.

[25]  G. V. Vande Woude,et al.  The Met proto-oncogene mesenchymal to epithelial cell conversion. , 1994, Science.

[26]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[27]  F. Bosch,et al.  Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes , 1990, Cell.

[28]  J. Berg.  DNA binding specificity of steroid receptors , 1989, Cell.

[29]  W. DeGrado,et al.  Molecular characterization of helix-loop-helix peptides. , 1992, Science.

[30]  T. Curran,et al.  Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. , 1990, Science.

[31]  A. E. Sippel,et al.  Chicken NFI/TGGCA proteins are encoded by at least three independent genes: NFI-A, NFI-B and NFI-C with homologues in mammalian genomes. , 1990, Nucleic acids research.

[32]  R. Tjian,et al.  Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40 , 1987, Nature.

[33]  P. Sharp.  Speculations on RNA splicing , 1981, Cell.

[34]  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.

[35]  H. Samuels,et al.  Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. , 1990, Molecular endocrinology.

[36]  W. Talbot,et al.  The drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily , 1991, Cell.

[37]  M. Watson,et al.  The NGFI-B gene, a transcriptionally inducible member of the steroid receptor gene superfamily: genomic structure and expression in rat brain after seizure induction , 1989, Molecular and cellular biology.

[38]  U. Schibler,et al.  Tissue-specific expression of the gene encoding hepatocyte nuclear factor 1 may involve hepatocyte nuclear factor 4. , 1991, Genes & development.

[39]  K. Zaret,et al.  Hepatocyte differentiation initiates during endodermal-mesenchymal interactions prior to liver formation. , 1991, Development.

[40]  E. Wagner,et al.  The human alpha-1-antitrypsin gene is efficiently expressed from two tissue-specific promotors in transgenic mice. , 1987, Nucleic acids research.

[41]  J. Lehmann,et al.  Genomic organization of the retinoic acid receptor gamma gene. , 1991, Nucleic acids research.

[42]  J. Bard,et al.  The development of the mouse kidney--embryogenesis writ small. , 1992, Current opinion in genetics & development.

[43]  G. Schütz,et al.  Tissue‐specific DNaseI hypersensitive sites in the 5′‐flanking sequences of the tryptophan oxygenase and the tyrosine aminotransferase genes. , 1984, The EMBO journal.

[44]  R. Lovell-Badge,et al.  Widespread expression of human alpha 1-antitrypsin in transgenic mice revealed by in situ hybridization. , 1989, Genes & development.

[45]  M. Karin,et al.  Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene , 1984, Nature.

[46]  P. Gruss,et al.  Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. , 1990, Development.

[47]  S. Akira,et al.  A nuclear factor for IL‐6 expression (NF‐IL6) is a member of a C/EBP family. , 1990, The EMBO journal.

[48]  T. Magnuson,et al.  Physical mapping of the albino-deletion complex in the mouse to localize alf/hsdr-1, a locus required for neonatal survival. , 1992, Genomics.

[49]  E. Winnacker,et al.  Clusters of nuclear factor I binding sites identify enhancers of several papillomaviruses but alone are not sufficient for enhancer function. , 1989, Nucleic acids research.

[50]  G. Kelsey,et al.  Lessons from lethal albino mice. , 1993, Current opinion in genetics & development.

[51]  H. Weintraub,et al.  Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection. , 1990, Science.

[52]  D. Goodman,et al.  An in situ-hybridization study of the localization of retinol-binding protein and transthyretin messenger RNAs during fetal development in the rat. , 1989, Differentiation; research in biological diversity.

[53]  R. Cortese,et al.  LFB1 and LFB3 homeoproteins are sequentially expressed during kidney development. , 1992, Development.

[54]  D. Barlow,et al.  Pattern of serum protein gene expression in mouse visceral yolk sac and foetal liver. , 1984, The EMBO journal.

[55]  B. O’Malley,et al.  COUP-TF gene: a structure unique for the steroid/thyroid receptor superfamily. , 1990, Nucleic acids research.

[56]  P. Chambon,et al.  The directly repeated RG(G/T)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites for RAR, RXR, HNF-4, and ARP-1 homo- and heterodimers. , 1994, The Journal of biological chemistry.

[57]  L. Saxén.  Organogenesis of the kidney , 1987 .

[58]  V. Laudet,et al.  Evolution of the nuclear receptor gene superfamily. , 1992, The EMBO journal.

[59]  J. Darnell,et al.  Transcriptional control in hepatocytes of normal and c14CoS albino deletion mice. , 1992, The EMBO journal.

[60]  R. Pedersen,et al.  Cell fate, morphogenetic movement and population kinetics of embryonic endoderm at the time of germ layer formation in the mouse. , 1987, Development.

[61]  M. Mckeown,et al.  Relationship between the product of the Drosophila ultraspiracle locus and the vertebrate retinoid X receptor , 1990, Nature.

[62]  J. Wilkinson,et al.  Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities , 1993, Nature.

[63]  R. Cortese,et al.  The transcriptional regulation of liver-specific gene expression. , 1991, Oxford surveys on eukaryotic genes.

[64]  J. Darnell,et al.  The expression pattern of a Drosophila homolog to the mouse transcription factor HNF‐4 suggests a determinative role in gut formation. , 1993, The EMBO journal.

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

[66]  J. Bard,et al.  The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo , 1993, Mechanisms of Development.

[67]  M. Crossley,et al.  Recovery from hemophilia B Leyden: an androgen-responsive element in the factor IX promoter. , 1992, Science.

[68]  C. Nüsslein-Volhard,et al.  The origin of pattern and polarity in the Drosophila embryo , 1992, Cell.