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 epidermis for adhesion to laminin-332, plays critical roles in basement membrane organization during skin development. In the current study, we identify a role for α3β1 in promoting stability of nascent epidermal basement membranes through induction of fibulin-2, a matrix-associated protein that binds laminin-332. We demonstrate that mice lacking α3β1 in epidermis display ruptured basement membrane 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 basement membrane 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 laminin-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 basement membrane stability through fibulin-2 induction, both in neonatal skin and adult wounds.