This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jacquemin, P.
Right arrow Articles by Lemaigre, F. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jacquemin, P.
Right arrow Articles by Lemaigre, F. P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2000, p. 4445-4454, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Transcription Factor Hepatocyte Nuclear Factor 6 Regulates Pancreatic Endocrine Cell Differentiation and Controls Expression of the Proendocrine Gene ngn3

Patrick Jacquemin,1 Serge M. Durviaux,1 Jan Jensen,2 Catherine Godfraind,3 Gerard Gradwohl,4 François Guillemot,4 Ole D. Madsen,2 Peter Carmeliet,5 Mieke Dewerchin,5 Désiré Collen,5 Guy G. Rousseau,1 and Frédéric P. Lemaigre1,*

Hormone and Metabolic Research Unit, Université catholique de Louvain and Christian de Duve Institute of Cellular Pathology,1 and Department of Pathology, Université catholique de Louvain,3 1200 Brussels, Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, 3000 Leuven,5 Belgium; Department of Developmental Biology, Hagedorn Research Institute, 2820 Gentofte, Denmark2; and Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM, Université Louis Pasteur, 67404 Illkirch Cedex, C. U. Strasbourg, France4

Received 4 October 1999/Returned for modification 28 October 1999/Accepted 7 March 2000

Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors. During mouse development, HNF-6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells. We have investigated the role of HNF-6 in pancreas differentiation by inactivating its gene in the mouse. In hnf6-/- embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiation was impaired. The expression of neurogenin 3 (Ngn-3), a transcription factor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, we demonstrated that HNF-6 binds to and stimulates the ngn3 gene promoter. At birth, only a few endocrine cells were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and their beta  cells were deficient in glucose transporter 2 expression. Adult hnf6-/- mice were diabetic. Taken together, our data demonstrate that HNF-6 controls pancreatic endocrine differentiation at the precursor stage and identify HNF-6 as the first positive regulator of the proendocrine gene ngn3 in the pancreas. They also suggest that HNF-6 is a candidate gene for diabetes mellitus in humans.

* Corresponding author. Mailing address: Box 7529, 75 Ave. Hippocrate, B-1200 Brussels, Belgium. Phone: +32 2 764 7583. Fax: +32 2 764 7507. E-mail: lemaigre{at}horm.ucl.ac.be.

Molecular and Cellular Biology, June 2000, p. 4445-4454, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Kang, H. S., Kim, Y.-S., ZeRuth, G., Beak, J. Y., Gerrish, K., Kilic, G., Sosa-Pineda, B., Jensen, J., Foley, J., Jetten, A. M. (2009). Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic {beta}-Cell Development and Insulin Gene Expression. Mol. Cell. Biol. 29: 6366-6379 [Abstract] [Full Text]  
  • Miyatsuka, T., Li, Z., German, M. S. (2009). Chronology of Islet Differentiation Revealed By Temporal Cell Labeling. Diabetes 58: 1863-1868 [Abstract] [Full Text]  
  • Guo, T., Hebrok, M. (2009). Stem Cells to Pancreatic {beta}-Cells: New Sources for Diabetes Cell Therapy. Endocr. Rev. 30: 214-227 [Abstract] [Full Text]  
  • Nagaya, M., Katsuta, H., Kaneto, H., Bonner-Weir, S., Weir, G. C (2009). Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells. J Endocrinol 201: 37-47 [Abstract] [Full Text]  
  • Fontaniere, S., Duvillie, B., Scharfmann, R., Carreira, C., Wang, Z.-Q., Zhang, C.-X. (2008). Tumour suppressor menin is essential for development of the pancreatic endocrine cells. J Endocrinol 199: 287-298 [Abstract] [Full Text]  
  • White, P., Lee May, C., Lamounier, R. N., Brestelli, J. E., Kaestner, K. H. (2008). Defining Pancreatic Endocrine Precursors and Their Descendants. Diabetes 57: 654-668 [Abstract] [Full Text]  
  • Lynn, F. C., Skewes-Cox, P., Kosaka, Y., McManus, M. T., Harfe, B. D., German, M. S. (2007). MicroRNA Expression Is Required for Pancreatic Islet Cell Genesis in the Mouse. Diabetes 56: 2938-2945 [Abstract] [Full Text]  
  • Lynn, F. C., Smith, S. B., Wilson, M. E., Yang, K. Y., Nekrep, N., German, M. S. (2007). Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc. Natl. Acad. Sci. USA 104: 10500-10505 [Abstract] [Full Text]  
  • Lehner, F., Kulik, U., Klempnauer, J., Borlak, J. (2007). The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 21: 1445-1462 [Abstract] [Full Text]  
  • Ait-Lounis, A., Baas, D., Barras, E., Benadiba, C., Charollais, A., Nlend Nlend, R., Liegeois, D., Meda, P., Durand, B., Reith, W. (2007). Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas. Diabetes 56: 950-959 [Abstract] [Full Text]  
  • Ackermann, A. M, Gannon, M. (2007). Molecular regulation of pancreatic {beta}-cell mass development, maintenance, and expansion. J Mol Endocrinol 38: 193-206 [Abstract] [Full Text]  
  • Murtaugh, L. C. (2007). Pancreas and beta-cell development: from the actual to the possible. Development 134: 427-438 [Abstract] [Full Text]  
  • Tweedie, E., Artner, I., Crawford, L., Poffenberger, G., Thorens, B., Stein, R., Powers, A. C., Gannon, M. (2006). Maintenance of Hepatic Nuclear Factor 6 in Postnatal Islets Impairs Terminal Differentiation and Function of {beta}-Cells. Diabetes 55: 3264-3270 [Abstract] [Full Text]  
  • Maier, E. A., Dusing, M. R., Wiginton, D. A. (2006). Temporal Regulation of Enhancer Function in Intestinal Epithelium: A ROLE FOR ONECUT FACTORS. J. Biol. Chem. 281: 32263-32271 [Abstract] [Full Text]  
  • Plaisance, V., Abderrahmani, A., Perret-Menoud, V., Jacquemin, P., Lemaigre, F., Regazzi, R. (2006). MicroRNA-9 Controls the Expression of Granuphilin/Slp4 and the Secretory Response of Insulin-producing Cells. J. Biol. Chem. 281: 26932-26942 [Abstract] [Full Text]  
  • Beaudry, J.-B., Pierreux, C. E., Hayhurst, G. P., Plumb-Rudewiez, N., Weiss, M. C., Rousseau, G. G., Lemaigre, F. P. (2006). Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1{alpha} Are Required for Time-Specific Gene Expression during Liver Development.. Mol. Cell. Biol. 26: 6037-6046 [Abstract] [Full Text]  
  • Poll, A. V., Pierreux, C. E., Lokmane, L., Haumaitre, C., Achouri, Y., Jacquemin, P., Rousseau, G. G., Cereghini, S., Lemaigre, F. P. (2006). A vHNF1/TCF2-HNF6 Cascade Regulates the Transcription Factor Network That Controls Generation of Pancreatic Precursor Cells. Diabetes 55: 61-69 [Abstract] [Full Text]  
  • Rubins, N. E., Friedman, J. R., Le, P. P., Zhang, L., Brestelli, J., Kaestner, K. H. (2005). Transcriptional Networks in the Liver: Hepatocyte Nuclear Factor 6 Function Is Largely Independent of Foxa2. Mol. Cell. Biol. 25: 7069-7077 [Abstract] [Full Text]  
  • Habener, J. F., Kemp, D. M., Thomas, M. K. (2005). Minireview: Transcriptional Regulation in Pancreatic Development. Endocrinology 146: 1025-1034 [Abstract] [Full Text]  
  • Haumaitre, C., Barbacci, E., Jenny, M., Ott, M. O., Gradwohl, G., Cereghini, S. (2005). Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc. Natl. Acad. Sci. USA 102: 1490-1495 [Abstract] [Full Text]  
  • Harmon, E. B., Apelqvist, A. A., Smart, N. G., Gu, X., Osborne, D. H., Kim, S. K. (2004). GDF11 modulates NGN3+ islet progenitor cell number and promotes {beta}-cell differentiation in pancreas development. Development 131: 6163-6174 [Abstract] [Full Text]  
  • Pierreux, C. E., Vanhorenbeeck, V., Jacquemin, P., Lemaigre, F. P., Rousseau, G. G. (2004). The Transcription Factor Hepatocyte Nuclear Factor-6/Onecut-1 Controls the Expression of Its Paralog Onecut-3 in Developing Mouse Endoderm. J. Biol. Chem. 279: 51298-51304 [Abstract] [Full Text]  
  • Rausa, F. M. III, Hughes, D. E., Costa, R. H. (2004). Stability of the Hepatocyte Nuclear Factor 6 Transcription Factor Requires Acetylation by the CREB-binding Protein Coactivator. J. Biol. Chem. 279: 43070-43076 [Abstract] [Full Text]  
  • Briancon, N., Bailly, A., Clotman, F., Jacquemin, P., Lemaigre, F. P., Weiss, M. C. (2004). Expression of the {alpha}7 Isoform of Hepatocyte Nuclear Factor (HNF) 4 Is Activated by HNF6/OC-2 and HNF1 and Repressed by HNF4{alpha}1 in the Liver. J. Biol. Chem. 279: 33398-33408 [Abstract] [Full Text]  
  • Sheng, W., Yan, H., Rausa, F. M. III, Costa, R. H., Liao, X. (2004). Structure of the Hepatocyte Nuclear Factor 6{alpha} and Its Interaction with DNA. J. Biol. Chem. 279: 33928-33936 [Abstract] [Full Text]  
  • Smith, S. B., Watada, H., German, M. S. (2004). Neurogenin3 Activates the Islet Differentiation Program while Repressing Its Own Expression. Mol. Endocrinol. 18: 142-149 [Abstract] [Full Text]  
  • 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. (2003). Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum Mol Genet 12: 3307-3314 [Abstract] [Full Text]  
  • Haumaitre, C., Reber, M., Cereghini, S. (2003). Functions of HNF1 Family Members in Differentiation of the Visceral Endoderm Cell Lineage. J. Biol. Chem. 278: 40933-40942 [Abstract] [Full Text]  
  • Kahan, B. W., Jacobson, L. M., Hullett, D. A., Ochoada, J. M., Oberley, T. D., Lang, K. M., Odorico, J. S. (2003). Pancreatic Precursors and Differentiated Islet Cell Types From Murine Embryonic Stem Cells: An In Vitro Model to Study Islet Differentiation. Diabetes 52: 2016-2024 [Abstract] [Full Text]  
  • Bouzin, C., Clotman, F., Renauld, J.-C., Lemaigre, F. P., Rousseau, G. G. (2003). The Onecut Transcription Factor Hepatocyte Nuclear Factor-6 Controls B Lymphopoiesis in Fetal Liver. J. Immunol. 171: 1297-1303 [Abstract] [Full Text]  
  • Suzuki, A., Iwama, A., Miyashita, H., Nakauchi, H., Taniguchi, H. (2003). Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 130: 2513-2524 [Abstract] [Full Text]  
  • Watada, H., Scheel, D. W., Leung, J., German, M. S. (2003). Distinct Gene Expression Programs Function in Progenitor and Mature Islet Cells. J. Biol. Chem. 278: 17130-17140 [Abstract] [Full Text]  
  • Suzuki, A., Nakauchi, H., Taniguchi, H. (2003). Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells. Proc. Natl. Acad. Sci. USA 100: 5034-5039 [Abstract] [Full Text]  
  • Clotman, F., Lannoy, V. J., Reber, M., Cereghini, S., Cassiman, D., Jacquemin, P., Roskams, T., Rousseau, G. G., Lemaigre, F. P. (2003). The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129: 1819-1828 [Abstract] [Full Text]  
  • Popova, N. V., Teti, K. A., Wu, K. Q., Morris, R. J. (2003). Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis. Carcinogenesis 24: 417-425 [Abstract] [Full Text]  
  • Rausa, F. M., Tan, Y., Costa, R. H. (2003). Association between Hepatocyte Nuclear Factor 6 (HNF-6) and FoxA2 DNA Binding Domains Stimulates FoxA2 Transcriptional Activity but Inhibits HNF-6 DNA Binding. Mol. Cell. Biol. 23: 437-449 [Abstract] [Full Text]  
  • Gerrish, K., Cissell, M. A., Stein, R. (2001). The Role of Hepatic Nuclear Factor 1alpha and PDX-1 in Transcriptional Regulation of the pdx-1 Gene. J. Biol. Chem. 276: 47775-47784 [Abstract] [Full Text]  
  • Eeckhoute, J., Formstecher, P., Laine, B. (2001). Maturity-Onset Diabetes of the Young Type 1 (MODY1)-Associated Mutations R154X and E276Q in Hepatocyte Nuclear Factor 4{{alpha}} (HNF4{{alpha}}) Gene Impair Recruitment of p300, a Key Transcriptional Coactivator. Mol. Endocrinol. 15: 1200-1210 [Abstract] [Full Text]  
  • Lee, J. C., Smith, S. B., Watada, H., Lin, J., Scheel, D., Wang, J., Mirmira, R. G., German, M. S. (2001). Regulation of the Pancreatic Pro-Endocrine Gene Neurogenin3. Diabetes 50: 928-936 [Abstract] [Full Text]  
  • Nakamura, T., Kishi, A., Nishio, Y., Maegawa, H., Egawa, K., Wong, N. C. W., Kojima, H., Fujimiya, M., Arai, R., Kashiwagi, A., Kikkawa, R. (2001). Insulin Production in a Neuroectodermal Tumor that Expresses Islet Factor-1, But Not Pancreatic-Duodenal Homeobox 1. J. Clin. Endocrinol. Metab. 86: 1795-1800 [Abstract] [Full Text]  
  • Kim, S. K., Hebrok, M. (2001). Intercellular signals regulating pancreas development and function. Genes Dev. 15: 111-127 [Full Text]  
  • Lannoy, V. J., Rodolosse, A., Pierreux, C. E., Rousseau, G. G., Lemaigre, F. P. (2000). Transcriptional Stimulation by Hepatocyte Nuclear Factor-6. TARGET-SPECIFIC RECRUITMENT OF EITHER CREB-BINDING PROTEIN (CBP) or p300/CBP-ASSOCIATED FACTOR (p/CAF). J. Biol. Chem. 275: 22098-22103 [Abstract] [Full Text]  
  • Watada, H., Mirmira, R. G., Leung, J., German, M. S. (2000). Transcriptional and Translational Regulation of beta -Cell Differentiation Factor Nkx6.1. J. Biol. Chem. 275: 34224-34230 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»