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: Joanna Jacków, Andreas Schlosser, Raija Sormunen, Alexander Nyström, Cassian Sitaru, Kaisa Tasanen, Leena Bruckner-Tuderman, Claus-Werner Franzke
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 136 Issue 2 Pg. 516-525 (Feb 2016) ISSN: 1523-1747 [Electronic] United States
• PMID: 26967482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Collagen Type VII

Topics

• Animals
• Cell Membrane (metabolism)
• Cell Proliferation (physiology)
• Cell-Derived Microparticles (metabolism)
• Collagen Type VII (metabolism)
• Epidermis (metabolism, pathology)
• Humans
• Immunohistochemistry
• Keratinocytes (cytology, metabolism)
• Mice
• Models, Animal
• Protein Structure, Tertiary
• Wound Healing (physiology)