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245 words Main text: 6141 words Abbreviations: EMT, epithelial-mesenchymal transition; GLP-1,-2, glucagon-like peptide-1, -2; LKB1, liver kinase B1; OXM, oxyntomodulin; PJS, Peutz-Jehgers syndrome; PYY, peptide tyrosine tyrosine © 2014. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. D ise as e M od el s & M ec ha ni sm s D M M Ac ce pt ed m an us cr ip t http://dmm.biologists.org/lookup/doi/10.1242/dmm.014720 Access the most recent version at DMM Advance Online Articles. Posted 4 September 2014 as doi: 10.1242/dmm.014720 2 ABSTRACT Liver kinase B1 (LKB1/STK11) is a serine/threonine kinase and tumour suppressor mutated in Peutz-Jeghers Syndrome (PJS), a premalignant syndrome associated with the development of gastrointestinal polyps. Proglucagon -expressing entero-endocrine cells are involved in the control of glucose homeostasis and the regulation of appetite through the secretion of gut hormones including glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY). To determine the role of LKB1 in these cells, we bred mice bearing flox’d alleles of Lkb1 against animals carrying Cre recombinase under proglucagon promoter control. These mice (GluLKB1KO) were viable and displayed near normal growth rates and glucose homeostasis. However, they developed large polyps at the gastro-duodenal junction, and displayed premature mortality, from 120 days of age. Histological analysis of the polyps demonstrated that they had a PJS-like appearance with an arborizing smooth muscle core. Circulating GLP1 levels were normal in GluLKB1KO mice and the polyps expressed low levels of the peptide, similar to those in the neighbouring duodenum. Lineage tracing using a Rosa26tdRFP transgene revealed, unexpectedly, that enterocytes within the polyps were derived from non-proglucagon expressing precursors whereas connective tissue was largely derived from proglucagon-expressing precursors. Developmental studies in wild type mice suggest that a subpopulation of proglucagon-expressing cells undergo epithelialmesenchymal transition (EMT) to become smooth muscle-like cells. Thus, it is likely that polyps in the GluLKB1KO mice developed from a unique population of smooth muscle-like cells derived from a proglucagon-expressing precursor. The loss of LKB1 within this subpopulation appears sufficient to drive tumorigenesis. D ise as e M od el s & M ec ha ni sm s D M M Ac ce pt ed m an us cr ip t