title: Growth Retardation, Loss of Desmosomal Adhesion, and Impaired Tight Junction Function Identify a Unique Role of Plakophilin 1 In Vivo.
abstract: Desmosomes mediate strong intercellular adhesion through desmosomal cadherins that interact with intracellular linker proteins including plakophilins (PKPs) 1-3 to anchor the intermediate filaments. PKPs show overlapping but distinct expression patterns in the epidermis. So far, the contribution of individual PKPs in differentially regulating desmosome function is incompletely understood. To resolve the role of PKP1 we ablated the PKP1 gene. Here, we report that PKP1(-/-) mice were born at the expected mendelian ratio with reduced birth weight, but they otherwise appeared normal immediately after birth. However, their condition rapidly declined, and the mice died within 24 hours, developing fragile skin with lesions in the absence of obvious mechanical trauma. This was accompanied by sparse and small desmosomes. Newborn PKP1(-/-) mice showed disturbed tight junctions with an impaired inside-out barrier, whereas the outside-in barrier was unaffected. Keratinocytes isolated from these mice showed strongly reduced intercellular cohesion, delayed tight junction formation, and reduced transepithelial resistance and reduced proliferation rates. Our study shows a nonredundant and essential role of PKP1 in desmosome and tight junction function and supports a role of PKP1 in growth control, a function that is crucial in wound healing and epidermal carcinogenesis.
authors.affiliation: Institute of Molecular Medicine, Division of Pathobiochemistry, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rietscher
authors.affiliation: Institute of Molecular Medicine, Division of Pathobiochemistry, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Biocenter, Electron Microscopy, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hause
authors.affiliation: Biocenter, Electron Microscopy, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Annekatrin
authors.initials: A
authors.lastname: Rother
authors.affiliation: Institute of Molecular Medicine, Division of Pathobiochemistry, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Keil
authors.affiliation: Institute of Biology, University of Leipzig, Leipzig, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
authors.affiliation: Institute of Molecular Medicine, Division of Cell Biology, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glass
authors.affiliation: Department of Dermatology, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.affiliation: Institute of Molecular Medicine, Division of Pathobiochemistry, Martin Luther University Halle-Wittenberg, Halle, Germany. Electronic address: mechthild.hatzfeld@medizin.uni-halle.de.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Hatzfeld
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D063646:Carcinogenesis; D002448:Cell Adhesion; D049109:Cell Proliferation; D003896:Desmosomes / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D051191:Plakophilins / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C495336:Pkp1 protein, mouse; D051191:Plakophilins