title: p120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas.
abstract: The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCζ. Although we observed reduced expression of adherens junction proteins E-cadherin, β-catenin, and α-catenin, p120 catenin family members p0071, ARVCF, and δ-catenin remained present at cell membranes in homozygous p120(f/f) pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development.
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: ahendle1@jhmi.edu.
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Hendley
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: elayne.provost@gmail.com.
authors.forename: Elayne
authors.initials: E
authors.lastname: Provost
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Jennifer.M.Bailey@uth.tmc.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: tiwang03@gmail.com.
authors.forename: Yue J
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: genetics85@gmail.com.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Cleveland
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: arielturnip@gmail.com.
authors.forename: Danielle
authors.initials: D
authors.lastname: Blake
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rossbittman@gmail.com.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Bittman
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jroeser10@gmail.com.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Roeser
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: amaitra@mdanderson.org.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: al.reynolds@vanderbilt.edu.
authors.forename: Albert B
authors.initials: AB
authors.lastname: Reynolds
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: leachs@mskcc.org.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010179:Pancreas / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D051178:alpha Catenin; D051176:beta Catenin; D000095002:Delta Catenin; C000722349:Ctnnd1 protein, mouse
keywords: Adherens junction; Branching morphogenesis; PKCζ; Pancreas development; Pancreatitis; Tubulogenesis; p120 Catenin