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.

  • Article
  • Published:

The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors

Nature Genetics volume 32, pages 128–134 (2002)Cite this article

Abstract

Pancreas development begins with the formation of buds at specific sites in the embryonic foregut endoderm. We used recombination-based lineage tracing in vivo to show that Ptf1a (also known as PTF1-p48) is expressed at these early stages in the progenitors of pancreatic ducts, exocrine and endocrine cells, rather than being an exocrine-specific gene as previously described. Moreover, inactivation of Ptf1a switches the character of pancreatic progenitors such that their progeny proliferate in and adopt the normal fates of duodenal epithelium, including its stem-cell compartment. Consistent with the proposal that Ptf1a supports the specification of precursors of all three pancreatic cell types, transgene-based expression of Pdx1, a gene essential to pancreas formation, from Ptf1a cis-regulatory sequences restores pancreas tissue to Pdx1-null mice that otherwise lack mature exocrine and endocrine cells because of an early arrest in organogenesis. These experiments provide evidence that Ptf1a expression is specifically connected to the acquisition of pancreatic fate by undifferentiated foregut endoderm.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Construction of targeting vector and transgene.
Figure 2: The Ptf1a gene is expressed in precursors of pancreatic islets, acini and ducts.
Figure 4: Abnormal pancreatic bud formation in Ptf1aCre/Cre R26R embryos.
Figure 3: Conversion from pancreatic to duodenal fates by inactivation of Ptf1a.
Figure 5: Partial restoration of pancreas development to Pdx1 null mutant mice by Ptf1a–Pdx1 transgene.

Similar content being viewed by others

References

  1. Lumelsky, N. et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 292, 1389–1394 (2001).

    Article  CAS  Google Scholar 

  2. Edlund, H. Developmental biology of the pancreas. Diabetes 50 (Suppl 1), S5–9 (2001).

    Article  CAS  Google Scholar 

  3. Kim, S.K. & Hebrok, M. Intercellular signals regulating pancreas development and function. Genes. Dev. 15, 111–127 (2001).

    Article  CAS  Google Scholar 

  4. Krapp, A. et al. The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. EMBO J. 15, 4317–4329 (1996).

    Article  CAS  Google Scholar 

  5. Adell, T. et al. Role of the basic helix-loop-helix transcription factor p48 in the differentiation phenotype of exocrine pancreas cancer cells. Cell. Growth. Differ. 11, 137–147 (2000).

    CAS  PubMed  Google Scholar 

  6. Rose, S.D., Swift, G.H., Peyton, M.J., Hammer, R.E. & MacDonald, R.J. The role of PTF1-p48 in pancreatic acinar gene expression. J. Biol. Chem. 276, 44018–44026 (2001).

    Article  CAS  Google Scholar 

  7. Krapp, A. et al. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes. Dev. 12, 3752–3763 (1998).

    Article  CAS  Google Scholar 

  8. Obata, J. et al. p48 subunit of mouse PTF1 binds to RBP-Jκ/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos. Genes. Cells 6, 345–360 (2001).

    Article  CAS  Google Scholar 

  9. Li, H. & Edlund, H. Persistent expression of Hlxb9 in the pancreatic epithelium impairs pancreatic development. Dev. Biol. 240, 247–253 (2001).

    Article  CAS  Google Scholar 

  10. Herrera, P.L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000).

    CAS  PubMed  Google Scholar 

  11. Gu, G., Dubauskaite, J. & Melton, D. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 (2000).

    Google Scholar 

  12. Gannon, M., Shiota, C., Postic, C., Wright, C.V. & Magnuson, M. Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis 26, 139–142 (2000).

    Article  CAS  Google Scholar 

  13. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  Google Scholar 

  14. 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  Google Scholar 

  15. 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 

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

    Article  CAS  Google Scholar 

  17. Zaret, K.S. Hepatocyte differentiation: from the endoderm and beyond. Curr. Opin. Genet. Dev. 11, 568–574 (2001).

    Article  CAS  Google Scholar 

  18. Matsumoto, K., Yoshitomi, H., Rossant, J. & Zaret, K.S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294, 559–563 (2001).

    Article  CAS  Google Scholar 

  19. Lammert, E., Cleaver, O. & Melton, D. Induction of pancreatic differentiation by signals from blood vessels. Science 294, 564–567 (2001).

    Article  CAS  Google Scholar 

  20. Gannon, M., Herrera, P.L. & Wright, C.V. Mosaic Cre-mediated recombination in pancreas using the pdx-1 enhancer/promoter. Genesis 26, 143–144 (2000).

    Article  CAS  Google Scholar 

  21. Hogan, B.L.M., Beddington, R., Constantin, F. & Lacy, E. Manipulating the Mouse Embryo. Cold Spring Harbor Lab. Press, Plainview, NY. (1994).

    Google Scholar 

  22. Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl Acad Sci. USA 93, 5860–5865 (1996).

    Article  CAS  Google Scholar 

  23. Sasaki, H. & Hogan, B.L. Enhancer analysis of the mouse HNF-3β gene: regulatory elements for node/notochord and floor plate are independent and consist of multiple sub-elements. Genes. Cells 1, 59–72 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Peshavaria, M. et al. XIHbox 8, an endoderm-specific Xenopus homeodomain protein, is closely related to a mammalian insulin gene transcription factor. Mol. Endocrinol. 8, 806–816 (1994).

    CAS  PubMed  Google Scholar 

  26. MacDonald, R.J., Przybyla, A.E. & Rutter, W.J. Isolation and in vitro translation of the messenger RNA coding for pancreatic amylase. J. Biol. Chem. 252, 5522–5528 (1977).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank B. Hogan, M. Magnuson, R. Stein, A. Means, Y. Fujitani, T. Fujiwara and members of the Wright lab for discussions; P. Soriano and R. Behringer for R26R mice; M. Lewandowski for the nls–Cre cassette; and A. Means for histology. Support from the ES Core, Animal Core and the DRTC at Vanderbilt University is also acknowledged. This work was funded in part by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists and Uehara Memorial Foundation (to Y.K.) and NIH NIDDK (to C.V.E.W.).

Author information

Author notes

  1. Yoshiya Kawaguchi

    Present address: Department of Surgery and Surgical Basic Science, School of Medicine, Kyoto University, 54-Shogoin Kawara-cho, Sakyo, Kyoto, 606-8507, Japan

Authors and Affiliations

  1. Department of Cell and Developmental Biology, Vanderbilt Developmental Biology Program, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, 37232-2175, Tennessee, USA

    Yoshiya Kawaguchi, Bonnie Cooper, Michael Ray & Christopher V.E. Wright

  2. Department of Medicine and Molecular Physiology and Biophysics, Vanderbilt Developmental Biology Program, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, 37232-2175, Tennessee, USA

    Maureen Gannon

  3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Raymond J. MacDonald

Authors
  1. Yoshiya Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bonnie Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maureen Gannon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raymond J. MacDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher V.E. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher V.E. Wright.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawaguchi, Y., Cooper, B., Gannon, M. et al. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet 32, 128–134 (2002). https://doi.org/10.1038/ng959

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng959

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