Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice

Nature Genetics volume 23, pages 71–75 (1999)Cite this article

Abstract

In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These buds fuse and develop into a complex organ composed of endocrine, exocrine and ductal components1,2. This developmental process depends upon an integrated network of transcription factors. Gene targeting experiments have revealed critical roles for Pdx1, Isl1, Pax4, Pax6 and Nkx2-2 (refs 3,4,5,6,7,8,9,10). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas11, although its role in pancreas development and function is unknown. To facilitate its study, we isolated the mouse HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventral pancreatic buds and mature β-cells in the islets of Langerhans express Hlxb9. In mice homologous for a null mutation of Hlxb9, the dorsal lobe of the pancreas fails to develop. The remnant Hlxb9–/– pancreas has small islets of Langerhans with reduced numbers of insulin-producing β-cells. Hlxb9–/– β-cells express low levels of the glucose transporter Glut2 and homeodomain factor Nkx 6-1. Thus, Hlxb9 is key to normal pancreas development and function.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hb9 in the islets of Langerhans of adult mice.
Figure 2: Hb9 is expressed in the developing pancreas.
Figure 3: The dorsal lobe of the pancreas fails to develop in Hlxb9–/– mice.
Figure 4: Expression of Pdx1, Isl1, Pax6 and Hnf3β in Hlxb9–/– mice.
Figure 5: Abnormal islets of Langerhans in Hlxb9–/– mice.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Githens, S. Differentiation and development of the pancreas in animals. in The Pancreas: Biology, Pathobiology, and Disease (ed. Go, V.L.W.) 21–55 (Raven Press, New York, 1993).

    Google Scholar 

  2. Slack, J.M. Developmental biology of the pancreas. Development 121, 1569–80 (1995).

    CAS  PubMed  Google Scholar 

  3. Jonsson, J., Carlsson, L., Edlund, T. & Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371, 606–609 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Ahlgren, U., Jonsson, J. & Edlund, H. The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 122, 1409–1416 (1996).

    CAS  PubMed  Google Scholar 

  5. Offield, M.F. et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995 (1996).

    CAS  PubMed  Google Scholar 

  6. Ahlgren, U., Pfaff, S.L., Jessell, T.M., Edlund, T. & Edlund, H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 385, 257–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G. & Gruss, P. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature 386, 399–402 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. St-Onge, L., Sosa-Pineda, B., Chowdhury, K., Mansouri, A. & Gruss, P. Pax6 is required for differentiation of glucagon-producing α-cells in mouse pancreas. Nature 387, 406–409 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Sander, M. et al. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 11, 1662–1673 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Sussel, L. et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells. Development 125, 2213–2221 (1998).

    CAS  PubMed  Google Scholar 

  11. Harrison, K.A., Druey, K.M., Deguchi, Y., Tuscano, J.M. & Kehrl, J.H. A novel human homeobox gene distantly related to proboscipedia is expressed in lymphoid and pancreatic tissues. J. Biol. Chem. 269, 19968–19975 (1994).

    CAS  PubMed  Google Scholar 

  12. Baubonis, W. & Sauer, B. Genomic targeting with purified Cre recombinase. Nucleic Acids Res. 21, 2025–2029 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gu, H., Zou, Y.R. & Rajewsky, K. Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting. Cell 73, 1155–1164 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Thaler, J. et al. Active suppression of interneuron programs within developing motor neurons revealed by the analysis of homeodomain factor HB9. Neuron (in press).

  15. Ross, A.J. et al. A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nature Genet. 20, 358–361 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Wu, K.L. et al. Hepatocyte nuclear factor 3β is involved in pancreatic β-cell- specific transcription of the pdx-1 gene. Mol. Cell. Biol. 17, 6002–6013 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thorens, B., Sarkar, H.K., Kaback, H.R. & Lodish, H.F. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and β-pancreatic islet cells. Cell 55, 281–290 (1988).

    Article  CAS  PubMed  Google Scholar 

  18. Jensen, J., Serup, P., Karlsen, C., Nielsen, T.F. & Madsen, O.D. mRNA profiling of rat islet tumors reveals Nkx 6.1 as a β-cell-specific homeodomain transcription factor. J. Biol. Chem. 271, 18749–18758 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Ahlgren, U., Jonsson, J., Jonsson, L., Simu, K. & Edlund, H. β-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes. Genes Dev. 12, 1763–1768 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim, S.K., Hebrok, M. & Melton, D.A. Notochord to endoderm signaling is required for pancreas development. Development 124, 4243–4252 (1997).

    CAS  PubMed  Google Scholar 

  21. Hebrok, M., Kim, S.K. & Melton, D.A. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12, 1705–1713 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Apelqvist, A., Ahlgren, U. & Edlund, H. Sonic hedgehog directs specialized mesoderm differentiation in the intestine and pancreas. Curr. Biol. 7, 801–804 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Rudnick, A., Ling, T.Y., Odagiri, H., Rutter, W.J. & German, M.S. Pancreatic β cells express a diverse set of homeobox genes. Proc. Natl Acad. Sci. USA 91, 12203–12207 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sander, M. & German, M.S. The β-cell transcription factors and development of the pancreas. J. Mol. Med. 75, 327–340 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Thor, S., Andersson, S.G., Tomlinson, A. & Thomas, J.B. A LIM-homeodomain combinatorial code for motor-neuron pathway selection. Nature 397, 76–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Pfaff, S.L., Mendelsohn, M., Stewart, C.L., Edlund, T. & Jessell, T.M. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84, 309–320 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Rust for excellent editorial assistance, A. Walsh for performing the blastocyte injection and A.S. Fauci for continued support.

Author information

Authors and Affiliations

  1. Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Kathleen A. Harrison & John H. Kehrl

  2. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Hua Gu

  3. Gene Expression Laboratory, the Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Joshua Thaler & Samuel L. Pfaff

Authors
  1. Kathleen A. Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua Thaler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel L. Pfaff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hua Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John H. Kehrl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John H. Kehrl.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Harrison, K., Thaler, J., Pfaff, S. et al. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet 23, 71–75 (1999). https://doi.org/10.1038/12674

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/12674

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing