The zonula occludens protein family regulates the hepatic barrier system in the murine liver

Itoh, Masahiko; Terada, Misao; Sugimoto, Hiroyuki

doi:10.1016/j.bbadis.2020.165994

Cited by 18 publications

(16 citation statements)

References 40 publications

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“…In the recent reports, Alb-Cre Tjp2-ko mice were born with healthy liver and exhibited hepatocyte injury only when fed with a high bile acid diet [10,11]. In our study, TJP2 deficiency J o u r n a l P r e -p r o o f in human hepatocytes exhibits disruption of the canalicular membrane when differentiated into mature hepatocytes with bile acid synthesis, suggesting that bile acid plays a crucial role in TJP2 deficiency of human hepatocytes.…”

Section: Morphological Analysis Of Ihep With Tjp2 Deficiency Demonstrated Distorted Cellular Polaritysupporting

confidence: 60%

“…However, mice lacking TJP2 were embryonic lethal at the early developmental stage and were not feasible for mechanistic investigation. Recent two studies investigated conditional knockout mouse models by using the ALB-Cre TJP2-flox system [10,11]. Itoh et al described no significant morphological and functional changes in the Tjp2 deficient liver.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“…Two recent studies investigated conditional knockout mouse models by using the ALB-Cre TJP2-flox system. 10 , 11 Itoh et al. 10 described no significant morphological and functional changes in the Tjp2-deficient liver.…”

Section: Introductionmentioning

confidence: 99%

“… 10 , 11 Itoh et al. 10 described no significant morphological and functional changes in the Tjp2-deficient liver. Xu et al.…”

Section: Introductionmentioning

confidence: 99%

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Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency

Ogawa

et al. 2022

JHEP Reports

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A, Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency, JHEP Reports (2022), doi: https://doi.org/10.1016/j.jhepr.2022.100446. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Morphological Analysis Of Ihep With Tjp2 Deficiency Demonstrated Distorted Cellular Polaritysupporting

confidence: 60%

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“… 10 , 11 Itoh et al. 10 described no significant morphological and functional changes in the Tjp2-deficient liver. Xu et al.…”

Section: Introductionmentioning

confidence: 99%

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Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency

Ogawa

et al. 2022

JHEP Reports

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“…Hepatocytes exhibit a unique cellular polarity and the maintenance of cellular polarity is essential for many functions of hepatocytes ( Gissen and Arias, 2015 ). In a recent study, Itoh et al inactivated the TJP2/ZO-2 gene in alive mouse livers and observed that the cellular polarity was compromised ( Itoh et al, 2021 ). The specific transporters localized at basolateral and apical membrane domains are responsible for the uptake and secretion processes ( Stapelbroek et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients

Tang

Tan

Deng

et al. 2021

Front. Cell Dev. Biol.

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Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.

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Intracellular Traffic and Non-canonical Roles of ZO-2 Protein

et al. 2022

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The zonula occludens protein family regulates the hepatic barrier system in the murine liver

Cited by 18 publications

References 40 publications

Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency

Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency

Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients

Intracellular Traffic and Non-canonical Roles of ZO-2 Protein

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