The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas.

Murine hepatocyte nuclear factor-3 beta (HNF-3 beta) protein is a member of a large family of developmentally regulated transcription factors that share homology in the winged helix/fork head DNA binding domain and that participate in embryonic pattern formation. HNF-3 beta also mediates cell-specific transcription of genes important for the function of hepatocytes, intestinal and bronchiolar epithelial, and pancreatic acinar cells. We have previously identified a liver-enriched transcription factor, HNF-6, which is required for HNF-3 beta promoter activity and also recognizes the regulatory region of numerous hepatocyte-specific genes. In this study we used the yeast one-hybrid system to isolate the HNF-6 cDNA, which encodes a cut-homeodomain-containing transcription factor that binds with the same specificity as the liver HNF-6 protein. Cotransfection assays demonstrate that HNF-6 activates expression of a reporter gene driven by the HNF-6 binding site from either the HNF-3 beta or transthyretin (TTR) promoter regions. We used interspecific backcross analysis to determine that murine Hnf6 gene is located in the middle of mouse chromosome 9. In situ hybridization studies of staged specific embryos demonstrate that HNF-6 and its potential target gene, HNF-3 beta, are coexpressed in the pancreatic and hepatic diverticulum. More detailed analysis of HNF-6 and HNF-3 beta's developmental expression patterns provides evidence of colocalization in hepatocytes, intestinal epithelial, and in the pancreatic ductal epithelial and exocrine acinar cells. The expression patterns of these two transcription factors do not overlap in other endoderm-derived tissues or the neurotube. We also found that HNF-6 is also abundantly expressed in the dorsal root ganglia, the marginal layer, and the midbrain. At day 18 of gestation and in the adult pancreas, HNF-6 and HNF-3 beta transcripts colocalize in the exocrine acinar cells, but their expression patterns diverge in other pancreatic epithelium. HNF-6, but not HNF-3 beta, expression continues in the pancreatic ductal epithelium, whereas only HNF-3 beta becomes restricted to the endocrine cells of the islets of Langerhans. We discuss these expression patterns with respect to specification of hepatocytes and differentiation of the endocrine and exocrine pancreas.

[1]  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.

[2]  L. Lim,et al.  The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Zaret,et al.  In vivo footprinting with limiting amounts of embryo tissues: a role for C/EBP beta in early hepatic development. , 1997, Methods.

[4]  T. Hansen,et al.  Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3) , 1996, Nature.

[5]  R. Costa,et al.  The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression , 1996, Molecular and cellular biology.

[6]  L. Lim,et al.  Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung. , 1996, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[7]  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.

[8]  F. Collins,et al.  Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene. , 1996, Genomics.

[9]  J. Paré,et al.  The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family , 1996, Molecular and cellular biology.

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

[11]  J. Whitsett,et al.  Hepatocyte nuclear factor 3 activates transcription of thyroid transcription factor 1 in respiratory epithelial cells , 1996, Molecular and cellular biology.

[12]  E. Dumonteil,et al.  Insulin gene: organisation, expression and regulation. , 1996, Diabetes & metabolism.

[13]  W. Knöchel,et al.  Five years on the wings of fork head , 1996, Mechanisms of Development.

[14]  B. Hogan,et al.  The chromosomal mapping of four genes encoding winged helix proteins expressed early in mouse development. , 1996, Genomics.

[15]  H. Edlund,et al.  The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. , 1996, Development.

[16]  B. Hogan,et al.  PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. , 1996, Development.

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

[18]  N. Copeland,et al.  The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9. , 1995, Genomics.

[19]  R. Costa,et al.  Cytokine regulation of the liver transcription factor hepatocyte nuclear factor-3 beta is mediated by the C/EBP family and interferon regulatory factor 1. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[20]  L. Rosenberg,et al.  In vivo cell transformation: neogenesis of beta cells from pancreatic ductal cells. , 1995, Cell transplantation.

[21]  J. Slack.  Developmental biology of the pancreas. , 1995, Development.

[22]  S. Frutiger,et al.  Binding sites for hepatocyte nuclear factor 3 beta or 3 gamma and pancreas transcription factor 1 are required for efficient expression of the gene encoding pancreatic alpha-amylase , 1995, Molecular and cellular biology.

[23]  R. Costa,et al.  Decreased expression of hepatocyte nuclear factor 3 alpha during the acute-phase response influences transthyretin gene transcription , 1995, Molecular and cellular biology.

[24]  J. Darnell,et al.  Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression , 1994, Molecular and cellular biology.

[25]  R. Lauro,et al.  The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis , 1994, Molecular and cellular biology.

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

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

[28]  J. Darnell,et al.  Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Thorgeirsson,et al.  Expression of hepatic transcription factors during liver development and oval cell differentiation , 1994, The Journal of cell biology.

[30]  R. Costa,et al.  The DNA-binding specificity of the hepatocyte nuclear factor 3/forkhead domain is influenced by amino-acid residues adjacent to the recognition helix , 1994, Molecular and cellular biology.

[31]  B. Hogan,et al.  HNF-3β as a regulator of floor plate development , 1994, Cell.

[32]  I. Herskowitz,et al.  Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. , 1993, Science.

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

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

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

[37]  Michael M. Wang,et al.  Molecular cloning of the olfactory neuronal transcription factor Olf-1 by genetic selection in yeast , 1993, Nature.

[38]  B. Stripp,et al.  The lung-specific CC10 gene is regulated by transcription factors from the AP-1, octamer, and hepatocyte nuclear factor 3 families , 1993, Molecular and cellular biology.

[39]  N. Sarvetnick,et al.  Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. , 1993, Development.

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

[41]  E. Lai,et al.  Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein , 1992, Molecular and cellular biology.

[42]  R. Costa,et al.  The restricted promoter activity of the liver transcription factor hepatocyte nuclear factor 3 beta involves a cell-specific factor and positive autoactivation , 1992, Molecular and cellular biology.

[43]  W. Rutter,et al.  Onset of cell-specific gene expression in the developing mouse pancreas. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

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

[45]  N. Copeland,et al.  Development and applications of a molecular genetic linkage map of the mouse genome. , 1991, Trends in genetics : TIG.

[46]  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.

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

[48]  R. Harland,et al.  Localization of specific mRNAs in Xenopus embryos by whole-mount in situ hybridization. , 1990, Development.

[49]  J. Darnell,et al.  Fetal and adult localization of C/EBP: evidence for combinatorial action of transcription factors in cell-specific gene expression. , 1990, Development.

[50]  U. Schibler,et al.  DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally , 1990, Cell.

[51]  N. Copeland,et al.  A molecular genetic linkage map of mouse chromosome 9 with regional localizations for the Gsta, T3g, Ets-1 and Ldlr loci. , 1989, Genetics.

[52]  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.

[53]  V. P. Collins,et al.  Transthyretin immunoreactivity in human and porcine liver, choroid plexus, and pancreatic islets. , 1989, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[54]  N. Copeland,et al.  Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus , 1982, Journal of virology.

[55]  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.

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

[57]  M. Stoffel,et al.  Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1) , 1996, Nature.

[58]  L. Lim,et al.  Hepatocyte Nuclear Factor 3 / fork head Homolog 11 Is Expressed in Proliferating Epithelial and Mesenchymal Cells of Embryonic and Adult Tissues , 1996 .

[59]  R. Stein,et al.  Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. , 1995, Development.

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

[61]  E. L. Green.  Linkage, recombination and mapping , 1981 .

[62]  L. B. Russell.  Definition of functional units in a small chromosomal segment of the mouse and its use in interpreting the nature of radiation-induced mutations. , 1971, Mutation research.