title: Protein O-mannosylation is crucial for E-cadherin-mediated cell adhesion.
abstract: In recent years protein O-mannosylation has become a focus of attention as a pathomechanism underlying severe congenital muscular dystrophies associated with neuronal migration defects. A key feature of these disorders is the lack of O-mannosyl glycans on α-dystroglycan, resulting in abnormal basement membrane formation. Additional functions of O-mannosylation are still largely unknown. Here, we identify the essential cell-cell adhesion glycoprotein epithelial (E)-cadherin as an O-mannosylated protein and establish a functional link between O-mannosyl glycans and cadherin-mediated cell-cell adhesion. By genetically and pharmacologically blocking protein O-mannosyltransferases, we found that this posttranslational modification is essential for preimplantation development of the mouse embryo. O-mannosylation-deficient embryos failed to proceed from the morula to the blastocyst stage because of defects in the molecular architecture of cell-cell contact sites, including the adherens and tight junctions. Using mass spectrometry, we demonstrate that O-mannosyl glycans are present on E-cadherin, the major cell-adhesion molecule of blastomeres, and present evidence that this modification is generally conserved in cadherins. Further, the use of newly raised antibodies specific for an O-mannosyl-conjugated epitope revealed that these glycans are present on early mouse embryos. Finally, our cell-aggregation assays demonstrated that O-mannosyl glycans are crucial for cadherin-based cell adhesion. Our results redefine the significance of O-mannosylation in humans and other mammals, showing the immense impact of cadherins on normal as well as pathogenic cell behavior.
authors.affiliation: Centre for Organismal Studies, Cell Chemistry and Center for Molecular Biology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Lommel
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Winterhalter
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.forename: Maik
authors.initials: M
authors.lastname: Dahlhoff
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
authors.forename: Markus F
authors.initials: MF
authors.lastname: Bartels
authors.forename: Ingrid
authors.initials: I
authors.lastname: Renner-Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruppert
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Sabine
authors.initials: S
authors.lastname: Strahl
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004285:Dogs; D004622:Embryo, Mammalian / Q000166:cytology* / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D061985:Madin Darby Canine Kidney Cells; D008358:Mannose / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D011134:Polysaccharides / Q000378:metabolism
chemical_list: D015820:Cadherins; D017931:DNA Primers; D011134:Polysaccharides; D008358:Mannose
keywords: O-glycans; POMT1; POMT2; mouse preimplantation development; protein-glycosylation