Reduced fibulin-2 contributes to loss of basement membrane integrity and skin blistering in mice lacking integrin ?3?1 in the epidermis.

ABSTRACT: Deficient epidermal adhesion is a hallmark of blistering skin disorders and chronic wounds, implicating integrins as potential therapeutic targets. Integrin ?3?1, 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 ?3?1 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 ?3?1 in the epidermis display ruptured BM beneath neo-epidermis of wounds, characterized by extensive blistering. This junctional blistering phenocopies defects reported in newborn ?3-null mice, as well as in human patients with ?3 gene mutations, indicating that the developmental role of ?3?1 in BM organization is recapitulated during wound healing. Mice lacking epidermal ?3?1 also have reduced fibulin-2 expression, and fibulin-2-null mice display perinatal skin blisters similar to those in ?3?1-deficient mice. Interestingly, ?3-null wound epidermis or keratinocytes also show impaired processing of the LN-332 ?2 chain, although this defect was independent of reduced fibulin-2 and did not appear to cause blistering. Our findings indicate a role for integrin ?3?1 in BM stability through fibulin-2 induction, both in neonatal skin and in adult wounds.

SUBMITTER: Longmate WM 

PROVIDER: S-EPMC4020984 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature