title: Reduced fibulin-2 contributes to loss of basement membrane integrity and skin blistering in mice lacking integrin α3β1 in the epidermis.
abstract: Deficient epidermal adhesion is a hallmark of blistering skin disorders and chronic wounds, implicating integrins as potential therapeutic targets. Integrin α3β1, a major receptor in the epidermis for adhesion to laminin-332 (LN-332), has critical roles in basement membrane (BM) organization during skin development. In the current study we identify a role for α3β1 in promoting stability of nascent epidermal BMs through induction of fibulin-2, a matrix-associated protein that binds LN-332. We demonstrate that mice lacking α3β1 in the epidermis display ruptured BM beneath neo-epidermis of wounds, characterized by extensive blistering. This junctional blistering phenocopies defects reported in newborn α3-null mice, as well as in human patients with α3 gene mutations, indicating that the developmental role of α3β1 in BM organization is recapitulated during wound healing. Mice lacking epidermal α3β1 also have reduced fibulin-2 expression, and fibulin-2-null mice display perinatal skin blisters similar to those in α3β1-deficient mice. Interestingly, α3-null wound epidermis or keratinocytes also show impaired processing of the LN-332 γ2 chain, although this defect was independent of reduced fibulin-2 and did not appear to cause blistering. Our findings indicate a role for integrin α3β1 in BM stability through fibulin-2 induction, both in neonatal skin and in adult wounds.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York, USA.
authors.forename: Whitney M
authors.initials: WM
authors.lastname: Longmate
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Monichan
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Mon-Li
authors.initials: ML
authors.lastname: Chu
authors.affiliation: Nemours Biomedical Research and Nemours Cardiac Center, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsuda
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: My G
authors.initials: MG
authors.lastname: Mahoney
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York, USA. Electronic address: dipersm@mail.amc.edu.
authors.forename: C Michael
authors.initials: CM
authors.lastname: DiPersio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D014945:Wound Healing; D000097794:Kalinin
chemical_list: D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D039201:Integrin alpha3beta1; D034741:RNA, Small Interfering; D000097794:Kalinin; C084612:fibulin 2