title: Inappropriate cadherin switching in the mouse epiblast compromises proper signaling between the epiblast and the extraembryonic ectoderm during gastrulation.
abstract: Cadherin switching from E-cadherin (E-cad) to N-cadherin (N-cad) is a key step of the epithelial-mesenchymal transition (EMT) processes that occurs during gastrulation and cancer progression. We investigate whether cadherins actively participate in progression of EMT by crosstalk to signaling pathways. We apply ectopic cadherin switching before the onset of mouse gastrulation. Mutants with an induced E-cad to N-cad switch (Ncadki) die around E8.5. Severe morphological changes including a small epiblast, a rounded shape, an enlarged extra-embryonic compartment and lack of the amnion, combined with a massive cell detachment from the ectodermal layer are detected. In contrast to epiblast-specific E-cad depletion, gastrulation is initiated in Ncadki embryos, but patterning of the germ-layers is abnormal. An overall reduction in BMP signaling, expansion of Nodal and Eomes domains, combined with reduced Wnt3a expression at the primitive streak is observed. Our results show that in addition to cadherin-dependent adhesion, proper embryonic development requires E-cad mediated signaling function to facilitate a feedback loop that stabilizes Bmp4 and Bmp2 expression in the extraembryonic ectoderm and sustained downstream activity in the epiblast. Moreover, for proper morphogenesis a fine-tuned spatio-temporal control of cadherin switching is required during EMT at gastrulation to avoid premature cell detachment and migration.
authors.affiliation: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: M Felicia
authors.initials: MF
authors.lastname: Basilicata
authors.affiliation: Electron Microscopy Center, University Medicine Rostock, Strempelstr. 14, 18057 Rostock, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Frank
authors.affiliation: Epithelial Epigenetics and Development Lab, Institute of Medical Biology, A*STAR, Singapore.
authors.forename: Davor
authors.initials: D
authors.lastname: Solter
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, University of Erlangen-Nürnberg, Glückstr. 6, 91054 Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.affiliation: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.|Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, University of Erlangen-Nürnberg, Glückstr. 6, 91054 Erlangen, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Stemmler
mesh_terms: D000818:Animals; D019521:Body Patterning; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D004475:Ectoderm / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D005260:Female; D054262:Gastrulation; D005855:Germ Layers / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D011247:Pregnancy
chemical_list: C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D015820:Cadherins; C000611838:Cdh1 protein, mouse; C489083:Cdh2 protein, mouse