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Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus

Nature Genetics volume 30, pages 430–435 (2002)Cite this article

Abstract

Pbx1 is a member of the TALE (three–amino acid loop extension) class of homeodomain transcription factors1,2, which are components of hetero-oligomeric protein complexes thought to regulate developmental gene expression and to maintain differentiated cell states3. In vitro studies4,5 have shown that Pbx1 regulates the activity of Ipf1 (also known as Pdx1), a ParaHox homeodomain transcription factor6,7 required for the development and function of the pancreas in mice and humans8,9,10. To investigate in vivo roles of Pbx1 in pancreatic development and function, we examined pancreatic Pbx1 expression, and morphogenesis, cell differentiation and function in mice deficient11,12 for Pbx1. Pbx1−/− embryos had pancreatic hypoplasia and marked defects in exocrine and endocrine cell differentiation prior to death at embryonic day (E) 15 or E16. In these embryos, expression of Isl1 and Atoh5, essential regulators of pancreatic morphogenesis and differentiation, was severely reduced. Pbx1+/− adults had pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia. Thus, Pbx1 is essential for normal pancreatic development and function. Analysis of trans-heterozygous Pbx1+/− Ipf1+/− mice revealed in vivo genetic interactions between Pbx1 and Ipf1 that are essential for postnatal pancreatic function; these mice developed age-dependent overt diabetes mellitus, unlike Pbx1+/− or Ipf1+/− mice. Mutations affecting the Ipf1 protein may promote diabetes mellitus in mice and humans13,14,15,16. This study suggests that perturbation of Pbx1 activity may also promote susceptibility to diabetes mellitus.

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Figure 1: Pbx1 expression in embryonic and adult pancreas.
Figure 2: Defective pancreatic development in embryos deficient for Pbx1.
Figure 3: Defective endocrine and exocrine cell differentiation in Pbx1−/− mutants.
Figure 4: Differentiated islet cells are not generated in pancreatic explants from E10.5 Pbx1−/− embryos.
Figure 5: Impaired glucose homeostasis and insulin secretion in Pbx1-deficient male mice.
Figure 6: Islet defects in adult Pbx1+/− and trans-heterozygous Pbx1+/− Ipf1+/− mutants.

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Acknowledgements

We thank S. O'Gorman for crucial help with Pbx1 gene inactivation, C. Nicholas for expert technical assistance and members of the Kim laboratory, including E. Harmon, J. Heit and M.-L. Dequéant, for assistance with embryo dissections, immunohistochemistry, gene expression analysis and whole-mount photography. E. Harmon, E. Rulifson, C. Schnabel, A. Ko and Å. Apelqvist provided helpful criticism. A.Y.Z. was supported by a Medical Scholars Fellowship from the American Diabetes Association and the Stanford University Medical Alumni Scholars Program. M.L.C. was supported by National Institutes of Health grants. S.K.K. was supported by a Pew Biomedical Scholars award, a career development award from the American Diabetes Association and a National Institutes of Health grant.

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Author notes

  1. Licia Selleri

    Present address: Molecular Biology Program of Cornell University/Memorial Sloan-Kettering, Institute of Genetic Medicine, Cornell University Medical School, New York, USA

  2. Seung K. Kim and Licia Selleri: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Developmental Biology and Medicine (Division of Oncology), Beckman Center B300, Stanford University School of Medicine, Stanford, 94305-5329, California, USA

    Seung K. Kim, Joon S. Lee, Andrew Y. Zhang & Xueying Gu

  2. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

    Licia Selleri, Yakop Jacobs & Michael L. Cleary

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Correspondence to Seung K. Kim or Michael L. Cleary.

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Kim, S., Selleri, L., Lee, J. et al. Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. Nat Genet 30, 430–435 (2002). https://doi.org/10.1038/ng860

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