title: MMTV/LTR Promoter-Driven Transgenic Expression of EpCAM Leads to the Development of Large Pancreatic Islets.
abstract: Our previous work demonstrated an important role of EpCAM in the regulation of pancreatic cell adhesion, growth and differentiation. Here we investigated the consequences of human EpCAM (hEpCAM) overexpression under the control of the MMTV-LTR promoter, known to drive robust gene expression in a number of ductal epithelia, including the pancreas. In this animal model (MMTV-hEpCAM) we uncovered a striking pancreatic phenotype exhibiting a 12-fold increase in the islet cell mass, with normal expression patterns of insulin and the transcription factor PDX-1. Intriguingly, these large islet clusters revealed an altered architectural organization of α- and δ-cells that appeared interspersed with β-cells in the islet cores. This suggests an effect of the hEpCAM transgene on the function of other cell adhesion molecules that we have previously shown to regulate islet cell type segregation. Consistent with this finding, we show that the pancreatic epithelium in MMTV-hEpCAM transgenic mice exhibits a redistribution of β-catenin, a known regulator of E-cadherin-mediated adhesions. Collectively, these results provide an important in vivo validation of hEpCAM signaling properties in normal epithelia and offer unique opportunities to further explore the function of this glycoprotein in select pancreatic cell lineages to elicit islet cell expansion, and/or regeneration in diabetes.
authors.affiliation: Department of Medicine, Diabetes & Obesity Center of Excellence, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington (JRV, WY, VC)
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Vercollone
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (MB, SVL).
authors.forename: Maarten
authors.initials: M
authors.lastname: Balzar
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (MB, SVL).
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Litvinov
authors.affiliation: Department of Medicine, Diabetes & Obesity Center of Excellence, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington (JRV, WY, VC)
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Medicine, Diabetes & Obesity Center of Excellence, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington (JRV, WY, VC)
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cirulli
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D015870:Gene Expression; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020079:Terminal Repeat Sequences / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule
keywords: CD326; EpCAM; MMTV; diabetes; pancreatic islets; β-cells