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 p120f/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.

p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia

“…p120 f/f , C iMist1 ; p120 wt/wt , C iMist1 ; p120 f/wt , and C iMist1 ; p120 f/f mice displayed normal pancreatic histology 2–4 months post tamoxifen injection (Figure S1B). Similar to what we previously reported for C Pdx1 ; p120 f/f mice 10 months of age (29), a subset of C iMist1 ; p120 f/f mice 12 months post tamoxifen injection exhibited pancreatitis and ADM (Figure S1B). …”

“…Biallelic loss of p120 catenin during pancreas development promotes apical epithelial cell extrusion, and luminal cell extrusion has also been reported with p120 catenin loss in developing kidney and MDCK cysts (29,36). Given the abundant apical and basal extrusion observed in KC iMist1 ; p120 f/f pancreata, we next sought to interrogate the extrusion behavior of adult pancreatic cells lacking p120 catenin in an experimental model of acute pancreatitis.…”

“…Previously, using C Pdx1 ; p120 f/f mice, we reported that p120 catenin is required for proper tubulogenesis and cell-type specification during pancreas development (29). To determine the function of p120 catenin in adult mouse pancreas in the absence of a confounding developmental phenotype, we crossed transgenic mice harboring floxed alleles of p120 catenin (p120 f ) (21) with Mist1 CreER/+ (C iMist1 ) mice (20).…”

“…Previously, we and others have demonstrated that p120 catenin loss results in immune cell infiltration and inflammation, which is mediated in part by Nuclear factor-kB (NF-kB) activation (29,31). We next queried whether NF-kB signaling contributed to formation of ADM/PanIN/fibrostroma in KC iMist1 ; p120 f/f mice.…”

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…In addition to cell–matrix connections, E-cadherin-based cell–cell adhesions have important functions in maintaining the acinar cell phenotype. E-cadherin stability in epithelial cells is regulated by p120 catenin and deletion of this protein in epithelial lineages of the developing pancreas in mice leads to ADM and PanIN1A 74 .…”