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Gene Review

Hnf1b  -  HNF1 homeobox B

Mus musculus

Synonyms: AI385728, AI987804, HNF-1-beta, HNF-1B, HNF-1Beta, ...
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Disease relevance of Tcf2

  • To assess the possible involvement of HNF1 and/or vHNF1 as transcriptional regulators in the early steps of visceral endoderm differentiation, we have analyzed the expression pattern of both factors both in vitro during differentiation of murine F9 embryonal carcinoma cells and in vivo during early postimplantation mouse development [1].
  • METHODS: We have developed a nested RT-PCR assay that exploits the presence of ectopic HNF-1 beta transcripts in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines derived from subjects carrying HNF-1 beta splice site mutations [2].
  • In this report, we found a novel missense mutation in the HNF-1 beta gene in a patient with neonatal cholestasis and liver dysfunction together with the common features of MODY5 [3].
  • HNF1-null mutant mice, with a wild-type vHNF1 gene, develop normally, but die within a few weeks of birth with severe liver and kidney failure [4].
  • Comprehensive search for HNF-1beta-regulated genes in mouse hepatoma cells perturbed by transcription regulatory factor-targeted RNAi [5].

High impact information on Tcf2

  • HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro [6].
  • In contrast, exclusive expression of HNF-1 beta is associated with repression of a subset of hepatocyte-specific genes in the dedifferentiated hepatocyte cell line C2, differentiated F9 cells, in somatic hybrids between hepatocytes and fibroblasts, and in the lung [6].
  • This is associated with abnormal development of primary cilia at the apical pole of the duct cells and with reduced expression of a set of genes involved in polycystic diseases, namely those coding for HNF-1beta and for the cilium-associated proteins polyductin/fibrocystin and cystin [7].
  • Based on its expression pattern we inferred that HNF-1beta is a likely candidate for directly activating Hnf3g gene expression during development [8].
  • Tcf2-deficient mice die before gastrulation because of defective visceral endoderm formation [9].

Biological context of Tcf2

  • The promoter region of Tcf2 gene was sequenced in NSY, non-obese diabetic (NOD) and control C3H/He mice [10].
  • By using a novel single nucleotide polymorphism (SNP) in the coding sequence, the chromosomal location of Tcf2, encoding hepatic nuclear factor (HNF)-1beta, was determined in F2 intercrosses between Nagoya-Shibata-Yasuda (NSY) mice, an animal model of type 2 diabetes, and control C3H/He mice [10].
  • Our results also provide evidence of a posttranscriptional level of control of vHNF1 and HNF1 gene expression during development, in addition to the spatial restriction in transcription [1].
  • Taken together, these data suggest that vHNF1 participates as a regulatory factor in the initial transcriptional activation of the target genes in the visceral endoderm of the yolk sac, whereas the later appearance of HNF1 could be required for maintenance of their expression [1].
  • At 6-7.5 days of gestation, high levels of vHNF1 mRNA are present in the visceral extraembryonic endoderm, which co-localize with transcripts of the transthyretin gene [1].

Anatomical context of Tcf2

  • Our results highlight the requirement of Tcf2 for ensuring both accurate expression of key regulator molecules in the stomach-duodenal epithelium and proper acquisition of the pancreatic fate [9].
  • The extent of heterodimerization may be regulated in a tissue-specific way because freely exchangeable heterodimers are formed in Jurkat T cells transfected with HNF-1 alpha and HNF-1 beta, whereas in liver cells stable homodimers are present [6].
  • We show that, at E13-E18, the embryonic stage during which the major burst of beta-cell neogenesis takes place, pancreatic duct cells express Hnf1beta, the product of the maturity-onset diabetes of the young type 5 (MODY5) gene [11].
  • The morphology of the intrahepatic bile ducts was identical to that seen in mice whose Hnf1beta gene has been conditionally inactivated in the liver [12].
  • Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF1beta (or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic beta-cells [13].

Associations of Tcf2 with chemical compounds


Regulatory relationships of Tcf2

  • Alterations in the ratio of HNF-1 alpha to HNF-1 beta along the length of the intestine may influence HNF-1 dimer formation and expression of target genes [16].
  • Furthermore, we found that HNF6 can stimulate the Hnf1beta promoter [12].

Other interactions of Tcf2

  • Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas [11].
  • A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells [17].
  • Analysis of differentiation markers confirms that vHNF1 is part of a genetic network that directs the expression of HNF4 and downstream endodermal genes [18].
  • Distinct spatial expressions patterns were detected along the length of the small intestine for PDX-1, Cdx-2, GATA-4, GATA-5, GATA-6, HNF-1alpha, HNF-1beta and CDP transcription factor genes [19].
  • Quantitation shows that the relative ratio of HNF-1 alpha to HNF-1 beta mRNAs appears lower in the colon, where AFP is not expressed [16].

Analytical, diagnostic and therapeutic context of Tcf2


  1. Expression patterns of vHNF1 and HNF1 homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles. Cereghini, S., Ott, M.O., Power, S., Maury, M. Development (1992) [Pubmed]
  2. Abnormal splicing of hepatocyte nuclear factor-1 beta in the renal cysts and diabetes syndrome. Harries, L.W., Ellard, S., Jones, R.W., Hattersley, A.T., Bingham, C. Diabetologia (2004) [Pubmed]
  3. Promoter-specific repression of hepatocyte nuclear factor (HNF)-1 beta and HNF-1 alpha transcriptional activity by an HNF-1 beta missense mutant associated with Type 5 maturity-onset diabetes of the young with hepatic and biliary manifestations. Kitanaka, S., Miki, Y., Hayashi, Y., Igarashi, T. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  4. A set of polyclonal and monoclonal antibodies reveals major differences in post-translational modification of the rat HNF1 and vHNF1 homeoproteins. Chouard, T., Jeannequin, O., Rey-Campos, J., Yaniv, M., Traincard, F. Biochimie (1997) [Pubmed]
  5. Comprehensive search for HNF-1beta-regulated genes in mouse hepatoma cells perturbed by transcription regulatory factor-targeted RNAi. Tanaka, T., Tomaru, Y., Nomura, Y., Miura, H., Suzuki, M., Hayashizaki, Y. Nucleic Acids Res. (2004) [Pubmed]
  6. HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Mendel, D.B., Hansen, L.P., Graves, M.K., Conley, P.B., Crabtree, G.R. Genes Dev. (1991) [Pubmed]
  7. The transcription factor hepatocyte nuclear factor-6 controls the development of pancreatic ducts in the mouse. Pierreux, C.E., Poll, A.V., Kemp, C.R., Clotman, F., Maestro, M.A., Cordi, S., Ferrer, J., Leyns, L., Rousseau, G.G., Lemaigre, F.P. Gastroenterology (2006) [Pubmed]
  8. Transcriptional regulation in endoderm development: characterization of an enhancer controlling Hnf3g expression by transgenesis and targeted mutagenesis. Hiemisch, H., Schütz, G., Kaestner, K.H. EMBO J. (1997) [Pubmed]
  9. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Haumaitre, C., Barbacci, E., Jenny, M., Ott, M.O., Gradwohl, G., Cereghini, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Mapping and promoter sequencing of HNF-1beta gene in diabetes-prone and -resistant mice. Ueda, H., Ikegami, H., Kawaguchi, Y., Fujisawa, T., Nojima, K., Babaya, N., Yamada, K., Shibata, M., Yamato, E., Ogihara, T. Diabetes Res. Clin. Pract. (2001) [Pubmed]
  11. Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Maestro, M.A., Boj, S.F., Luco, R.F., Pierreux, C.E., Cabedo, J., Servitja, J.M., German, M.S., Rousseau, G.G., Lemaigre, F.P., Ferrer, J. Hum. Mol. Genet. (2003) [Pubmed]
  12. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Clotman, F., Lannoy, V.J., Reber, M., Cereghini, S., Cassiman, D., Jacquemin, P., Roskams, T., Rousseau, G.G., Lemaigre, F.P. Development (2002) [Pubmed]
  13. Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release. Wang, L., Coffinier, C., Thomas, M.K., Gresh, L., Eddu, G., Manor, T., Levitsky, L.L., Yaniv, M., Rhoads, D.B. Endocrinology (2004) [Pubmed]
  14. Adenovirus-mediated increase of HNF-3 levels stimulates expression of transthyretin and sonic hedgehog, which is associated with F9 cell differentiation toward the visceral endoderm lineage. Tan, Y., Costa, R.H., Kovesdi, I., Reichel, R.R. Gene Expr. (2001) [Pubmed]
  15. AR suppresses transcription of the alpha glycoprotein hormone subunit gene through protein-protein interactions with cJun and activation transcription factor 2. Jorgensen, J.S., Nilson, J.H. Mol. Endocrinol. (2001) [Pubmed]
  16. HNF-1 alpha and HNF-1 beta expression in mouse intestinal crypts. Serfas, M.S., Tyner, A.L. Am. J. Physiol. (1993) [Pubmed]
  17. A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells. Poll, A.V., Pierreux, C.E., Lokmane, L., Haumaitre, C., Achouri, Y., Jacquemin, P., Rousseau, G.G., Cereghini, S., Lemaigre, F.P. Diabetes (2006) [Pubmed]
  18. Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Coffinier, C., Thépot, D., Babinet, C., Yaniv, M., Barra, J. Development (1999) [Pubmed]
  19. Spatio-temporal patterns of intestine-specific transcription factor expression during postnatal mouse gut development. Fang, R., Olds, L.C., Sibley, E. Gene Expr. Patterns (2006) [Pubmed]
  20. vHNF1 is expressed in epithelial cells of distinct embryonic origin during development and precedes HNF1 expression. Ott, M.O., Rey-Campos, J., Cereghini, S., Yaniv, M. Mech. Dev. (1991) [Pubmed]
  21. Enamel matrix derivative stimulates core binding factor alpha1/Runt-related transcription factor-2 expression via activation of Smad1 in C2C12 cells. Takayama, T., Suzuki, N., Narukawa, M., Tokunaga, T., Otsuka, K., Ito, K. J. Periodontol. (2005) [Pubmed]
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