title: p120 Catenin-Mediated Stabilization of E-Cadherin Is Essential for Primitive Endoderm Specification.
abstract: E-cadherin-mediated cell-cell adhesion is critical for naive pluripotency of cultured mouse embryonic stem cells (mESCs). E-cadherin-depleted mESC fail to downregulate their pluripotency program and are unable to initiate lineage commitment. To further explore the roles of cell adhesion molecules during mESC differentiation, we focused on p120 catenin (p120ctn). Although one key function of p120ctn is to stabilize and regulate cadherin-mediated cell-cell adhesion, it has many additional functions, including regulation of transcription and Rho GTPase activity. Here, we investigated the role of mouse p120ctn in early embryogenesis, mESC pluripotency and early fate determination. In contrast to the E-cadherin-null phenotype, p120ctn-null mESCs remained pluripotent, but their in vitro differentiation was incomplete. In particular, they failed to form cystic embryoid bodies and showed defects in primitive endoderm formation. To pinpoint the underlying mechanism, we undertook a structure-function approach. Rescue of p120ctn-null mESCs with different p120ctn wild-type and mutant expression constructs revealed that the long N-terminal domain of p120ctn and its regulatory domain for RhoA were dispensable, whereas its armadillo domain and interaction with E-cadherin were crucial for primitive endoderm formation. We conclude that p120ctn is not only an adaptor and regulator of E-cadherin, but is also indispensable for proper lineage commitment.
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.|Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tim
authors.identifier: 0000-0002-2958-0104
authors.initials: T
authors.lastname: Pieters
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: Steven
authors.identifier: 0000-0002-5693-8570
authors.initials: S
authors.lastname: Goossens
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Haenebalcke
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Vanessa
authors.identifier: 0000-0003-4240-7098
authors.initials: V
authors.lastname: Andries
authors.affiliation: Department of Development and Regeneration, Laboratory of Molecular Biology (Celgen), University of Leuven, Leuven, Belgium.
authors.forename: Agata
authors.initials: A
authors.lastname: Stryjewska
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lemeire
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Tino
authors.identifier: 0000-0001-5897-2054
authors.initials: T
authors.lastname: Hochepied
authors.affiliation: Department of Development and Regeneration, Laboratory of Molecular Biology (Celgen), University of Leuven, Leuven, Belgium.|Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: Geert
authors.identifier: 0000-0001-5770-2458
authors.initials: G
authors.lastname: Berx
authors.affiliation: Department of Molecular Embryology, Max-Planck Institute of Immunobiology, Freiburg, Germany.|Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Stemmler
authors.affiliation: Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wirth
authors.affiliation: Mammalian Functional Genetics Laboratory, Division of Blood Cancers, Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University and Alfred Health Alfred Centre, Melbourne, Victoria, Australia.
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
authors.affiliation: Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van Hengel
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Inflammation Research Center, VIB, Ghent, Belgium.|Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: van Roy
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D051177:Catenins / Q000096:biosynthesis / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D058732:Embryoid Bodies / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004707:Endoderm / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells; D061848:Optical Imaging; D039904:Pluripotent Stem Cells / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; C000611838:Cdh1 protein, mouse; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin