TY - JOUR
T1 - P120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas
AU - Hendley, Audrey M.
AU - Provost, Elayne
AU - Bailey, Jennifer M.
AU - Wang, Yue J.
AU - Cleveland, Megan H.
AU - Blake, Danielle
AU - Bittman, Ross W.
AU - Roeser, Jeffrey C.
AU - Maitra, Anirban
AU - Reynolds, Albert B.
AU - Leach, Steven D.
N1 - Funding Information:
We cite our colleagues in Table S1 references for their generous contribution of antibodies including ARVCF and p0071, and Pdx1 given by Ilse Hoffman and Chris Wright, respectively. The authors wish to thank Qingfeng Zhu, Anzer Habibulla, and Mara Swaim for their invaluable assistance in maintaining mouse colonies and genotyping and Katherine Wu for her expert technical assistance. The authors are extremely grateful for helpful correspondences and technical guidance from Sapna Puri. We also give special thanks to Andrew Ewald for reading this manuscript. This study was supported by National Institutes of Health grant R01 DK56211 (S.D.L).
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
KW - Adherens junction
KW - Branching morphogenesis
KW - P120 Catenin
KW - PKCζ
KW - Pancreas development
KW - Pancreatitis
KW - Tubulogenesis
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U2 - 10.1016/j.ydbio.2014.12.010
DO - 10.1016/j.ydbio.2014.12.010
M3 - Article
C2 - 25523391
AN - SCOPUS:84923938835
SN - 0012-1606
VL - 399
SP - 41
EP - 53
JO - Developmental biology
JF - Developmental biology
IS - 1
ER -