Premium
Redundant role of catenins in maintaining tight junctional integrity
Author(s) -
PradhanSundd Tirthadipa,
Zhou Lili,
Jiang An,
Russell Jacquelyn Olivia,
Singh Sucha,
Poddar Minakshee,
Ranganathan Sarangarajan,
NejakBowen Kari,
Monga Satdarshan Singh Pal
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.305.3
Subject(s) - adherens junction , catenin , beta catenin , tight junction , plakoglobin , occludin , cadherin , microbiology and biotechnology , biology , wnt signaling pathway , actin cytoskeleton , alagille syndrome , hepatocyte , cholestasis , pathology , cytoskeleton , endocrinology , signal transduction , cell , medicine , genetics , in vitro
Adherens Junctional Complex (AJC) consisting of catenins and cadherins adhere the neighbouring cells by linking the actin cytoskeleton. B‐Catenin, a member of the catenin family, is required for cell‐cell adhesion as well as for canonical Wnt signaling. We have shown that loss of β‐catenin from the AJCs between adjacent hepatocytes or of g‐catenin from desmosomes, are well‐tolerated. In the present study we generated and characterized mice with liver‐specific knockout of β and γ‐catenin. Here, we used albumin‐cre and double floxed‐b‐catenin‐g‐catenin mice to generate hepatocyte and cholangiocyte specific double knockouts (DKO). These animals showed failure to thrive, increased morbidity and 80% of mice die in the first month after birth. The DKO mice exhibited increased serum bilirubin, alkaline phosphatase and cholesterol and mimicked progressive familial intrahepatic cholestasis (PFIC) like phenotype with inflammation, fibrosis and ductular reaction shown by histology and biochemical studies. Furthermore, AAV8‐cre mediated deletion of b‐ and g‐catenin from hepatocytes only, showed notable irregularities in serum and histology similar to DKOs. Next, we analyzed liver samples from PFIC patients (n=8). One patient showed substantial reduction of both β‐ and γ‐catenin proteins, along with loss of association to E‐cadherin. Molecular and histochemical analysis revealed significant reduction in expression of tight junction protein claudin‐2 and occludin, in both DKO mice and patient's samples. Thus, we have identified a notable cross talk between the catenins and TJ proteins which may be of essence in barrier function in the liver. Profound understanding of this regulation of tight junction protein stability by catenins will be useful in the context of liver developmental and pathophysiology. Support or Funding Information This research is supported by NIH. The presenting author is supported by T32 post doctoral training programme grant number 5T32DK063922‐13.