title: Generation of a Functional Non-Shedding Collagen XVII Mouse Model: Relevance of Collagen XVII Shedding in Wound Healing.
abstract: Collagen XVII is a hemidesmosomal anchorage molecule of basal keratinocytes that promotes stable epidermal-dermal adhesion. One unique feature of collagen XVII is that its collagenous ectodomain is constitutively released from the cell surface by a disintegrin and metalloproteinases (ADAMs) through cleavage within its juxtamembranous linker domain. The responsivity of shedding to environmental stimuli and the high stability of the released ectodomain in several tissues suggests functions in cell detachment during epidermal morphogenesis, differentiation, and regeneration, but its physiologic relevance remained elusive. To investigate this, we generated knock-in mice, which express a functional non-sheddable collagen XVII mutant, with a 41 amino acid deletion in the linker domain spanning all ADAM cleavage sites. These mice showed no macroscopic phenotypic changes, were fertile, and had a normal lifespan. Prevention of collagen XVII shedding interfered neither with skin development nor with epidermal adhesion and differentiation. However, it led to faster wound closure due to accelerated re-epithelialization at the wound edges where shedding of wild-type collagen XVII was strongly induced. Taken together, we have successfully generated a functional non-shedding collagen XVII mouse model, which represents a powerful tool to investigate the pathophysiologic relevance of ectodomain shedding during wound regeneration and cancer invasion.
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jacków
authors.affiliation: Core Facility Proteomic, Center for Systems Biology (ZBSA), Freiburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlosser
authors.affiliation: Biocenter Oulu, and Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nyström
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Cassian
authors.initials: C
authors.lastname: Sitaru
authors.affiliation: Department of Dermatology, Oulu Center for Cell-Matrix Research, PEDEGO and Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Tasanen
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany. Electronic address: claus-werner.franzke@uniklinik-freiburg.de.
authors.forename: Claus-Werner
authors.initials: CW
authors.lastname: Franzke
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D024143:Collagen Type VII / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D017434:Protein Structure, Tertiary; D014945:Wound Healing / Q000502:physiology*
chemical_list: D024143:Collagen Type VII