title: Pdx1 regulates pancreas tubulogenesis and E-cadherin expression.
abstract: Current efforts in developing treatments for diabetes focus on in vitro generation of functional β-cells for cell replacement therapies; however, these attempts have only been partly successful because factors involved in islet formation remain incompletely understood. The embryonic pancreas, which gives rise to β-cells, undergoes early epithelial rearrangements, including transient stratification of an initially monolayered epithelium, followed by microlumen formation and later resolution into branches. Within the epithelium, a multipotent progenitor cell (MPC) population is specified, giving rise to three important lineages: acinar, ductal and endocrine. Pdx1 is a transcription factor required for pancreas development and lineage specification; however, few Pdx1 targets that regulate pancreatogenesis have been identified. We find that pancreatic defects in Pdx1(-/-) embryos initiate at the time when the progenitor pool is specified and the epithelium should resolve into branches. Pdx1(-/-) microlumen diameters expand aberrantly, resulting in failure of epithelial tubulogenesis and ductal plexus formation. Pdx1(-/-) epithelial cell proliferation is decreased and the MPC pool is rapidly lost. We identify two conserved Pdx1 binding sites in the epithelial cadherin (E-cad, Cdh1) promoter, and show that Pdx1 directly binds and activates E-cad transcription. In addition, Pdx1 is required in vivo for maintenance of E-cad expression, actomyosin complex activity and cell shape. These findings demonstrate a novel link between regulators of epithelial architecture, specification of pancreatic cell fate and organogenesis.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Leilani
authors.initials: L
authors.lastname: Marty-Santos
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA ondine.cleaver@utsouthwestern.edu.
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015820:Cadherins / Q000096:biosynthesis* / Q000378:metabolism; D064200:Cdh1 Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D003920:Diabetes Mellitus / Q000196:embryology; D004848:Epithelium / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D010179:Pancreas / Q000002:abnormalities / Q000196:embryology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D015820:Cadherins; D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D018398:Homeodomain Proteins; D015534:Trans-Activators; D051176:beta Catenin; C084010:pancreatic and duodenal homeobox 1 protein; D000205:Actomyosin
keywords: Cdh1; E-cadherin; Endocrine; Epithelium; Lumen diameter; Microlumen; Pancreatic bud; Pdx1; Stratification; pMLC; β-catenin