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dc.contributor.authorPocaterra, Ariannaen
dc.contributor.authorSantinon, Giuliaen
dc.contributor.authorRomani, Patriziaen
dc.contributor.authorBrian, Ireneen
dc.contributor.authorDimitracopoulos, Andreaen
dc.contributor.authorGhisleni, Andreaen
dc.contributor.authorCarnicer-Lombarte, Alejandroen
dc.contributor.authorForcato, Mattiaen
dc.contributor.authorBraghetta, Paolaen
dc.contributor.authorMontagner, Marcoen
dc.contributor.authorGaluppini, Francescaen
dc.contributor.authorAragona, Mariacelesteen
dc.contributor.authorPennelli, Gianmariaen
dc.contributor.authorBicciato, Silvioen
dc.contributor.authorGauthier, Nilsen
dc.contributor.authorFranze, Kristianen
dc.contributor.authorDupont, Sirioen
dc.date.accessioned2019-04-05T23:31:46Z
dc.date.available2019-04-05T23:31:46Z
dc.identifier.issn1600-0641
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/291241
dc.description.abstractBACKGROUND & AIMS: In vitro, several data indicate that cell function can be regulated by the mechanical properties of cells and of the microenvironment. Cells measure these features by developing forces via their actomyosin cytoskeleton, and respond accordingly by transducing forces into biochemical signals that instruct cell behavior. Among these, the transcriptional coactivators YAP/TAZ recently emerged as key factors mediating multiple responses to actomyosin contractility. However, whether mechanical cues regulate adult liver tissue homeostasis, and whether this occurs through YAP/TAZ, remains largely unaddressed. METHODS & RESULTS: Here we show that the F-actin capping protein CAPZ is a critical negative regulator of actomyosin contractility and mechanotransduction. Capzb inactivation alters stress fiber and focal adhesion dynamics leading to enhanced myosin activity, increased cellular traction forces, and increased liver stiffness. In vitro, this rescues YAP from inhibition by a small geometry; in vivo, inactivation of Capzb in the adult mouse liver induces YAP activation in parallel to the Hippo pathway, causing extensive hepatocyte proliferation and leading to striking organ overgrowth. Moreover, Capzb is required for the maintenance of the differentiated hepatocyte state, for metabolic zonation, and for gluconeogenesis. In keeping with changes in tissue mechanics, inhibition of the contractility regulator ROCK, or deletion of the Yap1 mechanotransducer, reverse the phenotypes emerging in Capzb-null livers. CONCLUSIONS: These results indicate a previously unrecognized role for CAPZ in tuning the mechanical properties of cells and tissues, which is required in hepatocytes for the maintenance of the differentiated hepatocyte state and to regulate organ size. More in general, it indicates for the first time a physiological role of mechanotransduction in maintaining tissue homeostasis in mammals. LAY SUMMARY: The mechanical properties of cells and tissues (i.e. whether they are soft or stiff) are thought to be important regulators of cell behavior. A recent advancement in our understanding of these phenomena has been the identification of YAP and TAZ as key factors mediating the biological responses of cells to mechanical signals in vitro. However, whether the mechanical properties of cells and/or the mechanical regulation of YAP/TAZ are relevant for mammalian tissue physiology remains unknown. Here we challenge this issue by genetic inactivation of CAPZ, a protein that regulates the cytoskeleton, i.e. the cells' scaffold by which they sense mechanical cues. We found that inactivation of CAPZ alters cells' and liver tissue's mechanical properties, leading to YAP hyperactivation. In turn, this profoundly alters liver physiology, causing organ overgrowth, defects in liver cell differentiation and metabolism. These results reveal a previously uncharacterized role for mechanical signals for the maintenance of adult liver homeostasis.
dc.description.sponsorshipThis work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) Investigator Grant 15307, WCR (Worldwide Cancer Research) Grant 15-1192, CARIPARO Eccellenza Program 2017 and University of Padua BIRD Grant to SD, AIRC ‘Hard ROCK Café’ Fellowship to GS, Marie Sklodowska-Curie Individual Fellowship (796547) to AG, AIRC Special Program Molecular Clinical Oncology ‘5 per mille’ 10016 to SB, UK Medical Research Council and Sackler Foundation Doctoral Training Grant RG70550 to ACL, UK Medical Research Council Career Development Award G1100312/1 and an Isaac Newton Trust Research Grant 17.24(p) to KF.
dc.languageengen
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCAPZen
dc.subjectCapping proteinen
dc.subjectF-actin dynamicsen
dc.subjectGluconeogenesisen
dc.subjectGlucose metabolismen
dc.subjectHepatocyte cell fate maintenanceen
dc.subjectHippoen
dc.subjectLiver homeostasisen
dc.subjectMechanotransductionen
dc.subjectOrgan growthen
dc.subjectXenobiotic metabolismen
dc.subjectYAPen
dc.titleF-actin dynamics regulates mammalian organ growth and cell fate maintenance.en
dc.typeArticle
prism.publicationNameJournal of Hepatologyen
dc.identifier.doi10.17863/CAM.38420
dcterms.dateAccepted2019-02-22en
rioxxterms.versionofrecord10.1016/j.jhep.2019.02.022en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-02-22en
dc.contributor.orcidDimitracopoulos, Andrea [0000-0001-6776-4214]
dc.contributor.orcidFranze, Kristian [0000-0002-8425-7297]
dc.identifier.eissn1600-0641
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idIsaac Newton Trust (17.24(p))
pubs.funder-project-idMRC (G1100312)
cam.issuedOnline2019-03-14en
cam.orpheus.successThu Jan 30 10:47:35 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-03-14


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International