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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.

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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.

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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.).

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  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

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  1. Yoshiya Kawaguchi
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Correspondence to Christopher V.E. Wright.

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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

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