Targeted Disruption of the Gene Encoding Hepatocyte Nuclear Factor 3γ Results in Reduced Transcription of Hepatocyte-Specific Genes

ABSTRACT The winged helix transcription factor hepatocyte nuclear factor 3γ (HNF3γ) is expressed in embryonic endoderm and its derivatives liver, pancreas, stomach, and intestine, as well as in testis and ovary. We have generated mice carrying an Hnf3g-lacZ fusion which deletes most of the HNF3γ coding sequence as well as 5.5 kb of 3′ flanking region. Mice homozygous for the mutation are fertile, develop normally, and show no morphological defects. The mild phenotype change of the Hnf3g −/− mice can be explained in part by an upregulation of HNF3α and HNF3β in the liver of the mutant animals. Analysis of steady-state mRNA levels as well as transcription rates showed that levels of expression of several HNF3 target genes (phosphoenolpyruvate carboxykinase, transferrin, tyrosine aminotransferase) were reduced by 50 to 70%, indicating that HNF3γ is an important activator of these genes in vivo.

[1]  K. Kaestner,et al.  Transcriptional regulation in endoderm development: characterization of an enhancer controlling Hnf3g expression by transgenesis and targeted mutagenesis , 1997, The EMBO journal.

[2]  M. Yaniv,et al.  Hepatocyte Nuclear Factor 1 Inactivation Results in Hepatic Dysfunction, Phenylketonuria, and Renal Fanconi Syndrome , 1996, Cell.

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

[4]  A. Kahn,et al.  Transcription factors and aldolase B gene expression in microdissected renal proximal tubules and derived cell lines. , 1995, Experimental cell research.

[5]  P. Chomczyński,et al.  Substitution of chloroform by bromo-chloropropane in the single-step method of RNA isolation. , 1995, Analytical biochemistry.

[6]  K. Kaestner,et al.  Universal beta-galactosidase cloning vectors for promoter analysis and gene targeting. , 1994, Gene.

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

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

[9]  Wolfgang Schmid,et al.  Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[12]  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.

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

[14]  G. Schütz,et al.  The distal enhancer implicated in the developmental regulation of the tyrosine aminotransferase gene is bound by liver-specific and ubiquitous factors , 1993, Molecular and cellular biology.

[15]  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.

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

[17]  M. Rudnicki,et al.  Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development , 1992, Cell.

[18]  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.

[19]  K. Rajewsky,et al.  Generation and analysis of interleukin-4 deficient mice. , 1991, Science.

[20]  M. Muramatsu,et al.  Striking homology of the 'variable' N-terminal as well as the 'conserved core' domains of the mouse and human TATA-factors (TFIID). , 1991, Nucleic acids research.

[21]  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.

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

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

[24]  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.

[25]  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.

[26]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[27]  D. Kemp,et al.  Method for detection of specific RNAs in agarose gels by transfer to diazobenzyloxymethyl-paper and hybridization with DNA probes. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Hanson,et al.  Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. , 1997, Annual review of biochemistry.

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

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

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

[32]  B. Hames,et al.  Transcription and translation : a practical approach , 1984 .

[33]  W. Marzluff.  Transcription of RNA in isolated nuclei. , 1978, Methods in cell biology.

[34]  W. Marzluff.  Chapter 27. Transcription of RNA in Isolated Nuclei , 1978 .