title: Loss of α-catenin elicits a cholestatic response and impairs liver regeneration.
abstract: The liver is unique in its capacity to regenerate after injury, during which hepatocytes actively divide and establish cell-cell contacts through cell adhesion complexes. Here, we demonstrate that the loss of α-catenin, a well-established adhesion component, dramatically disrupts liver regeneration. Using a partial hepatectomy model, we show that regenerated livers from α-catenin knockdown mice are grossly larger than control regenerated livers, with an increase in cell size and proliferation. This increased proliferation correlated with increased YAP activation, implicating α-catenin in the Hippo/YAP pathway. Additionally, α-catenin knockdown mice exhibited a phenotype reminiscent of clinical cholestasis, with drastically altered bile canaliculi, elevated levels of bile components and signs of jaundice and inflammation. The disrupted regenerative capacity is a result of actin cytoskeletal disorganisation, leading to a loss of apical microvilli, dilated lumens in the bile canaliculi, and leaky tight junctions. This study illuminates a novel, essential role for α-catenin in liver regeneration.
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Keira Joann
authors.initials: KJ
authors.lastname: Herr
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Ying-hung Nicole
authors.initials: YH
authors.lastname: Tsang
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Joanne Wei En
authors.initials: JW
authors.lastname: Ong
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Lai Lai
authors.initials: LL
authors.lastname: Yap
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
authors.forename: Weimiao
authors.initials: W
authors.lastname: Yu
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A.
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.affiliation: 1] Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A [2] Department of Biology, MIT, Massachusetts, U.S.A [3] Institute for Medical Engineering and Science, MIT, Massachusetts, U.S.A.
authors.forename: James E
authors.initials: JE
authors.lastname: Dahlman
authors.affiliation: Department of Anatomy, National University of Singapore, Singapore.
authors.forename: Yee Gek
authors.initials: YG
authors.lastname: Chan
authors.affiliation: Department of Anatomy, National University of Singapore, Singapore.
authors.forename: Boon Huat
authors.initials: BH
authors.lastname: Bay
authors.affiliation: Translational Laboratory in Genetic Medicine, A*STAR, Singapore, Singapore.
authors.forename: Roshni
authors.initials: R
authors.lastname: Singaraja
authors.affiliation: 1] Koch Institute for Integrative Cancer Research, MIT, Massachusetts, U.S.A [2] Institute for Medical Engineering and Science, MIT, Massachusetts, U.S.A [3] Department of Chemical Engineering, MIT, Massachusetts, U.S.A [4] Department of Anaesthesiology, Children's Hospital Boston, Harvard Medical School, Massachusetts, U.S.A.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Skolkovo Institute of Science and Technology ul, Skolkovo, Russian Federation.
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.affiliation: Mechanobiology Institute, National University of Singapore, Singapore.
authors.forename: Virgile
authors.initials: V
authors.lastname: Viasnoff
authors.affiliation: 1] Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore [2] Department of Biochemistry School of Medicine National University of Singapore, Singapore [3] Cancer Science Institute National University of Singapore, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001648:Bile Canaliculi / Q000473:pathology / Q000648:ultrastructure; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002779:Cholestasis / Q000097:blood / Q000235:genetics*; D005260:Female; D022781:Hepatocytes / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000648:ultrastructure; D023421:Models, Animal; D010750:Phosphoproteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D051178:alpha Catenin / Q000172:deficiency / Q000235:genetics*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051178:alpha Catenin