641 Cell – collagen interactions through collagen-binding integrins are dispensable for murine development

Abstract

Collagens are the most abundant component of the extracellular matrix. They largely contribute to tissue mechanical stability. In the skin, integrins α1β1, α2β1, α11β1 are the three main collagen receptors facilitating cell to collagen contact. Using single and double knockout mouse models lacking collagen-binding integrins, we were able to delineate their individual functions and functional redundancy. Here we address the overall significance of integrin-mediated direct interaction of cells with collagens. We generated triple knockout (tKO) mice globally lacking α1β1, α2β1 and α11β1 integrins. These mice develop and are born after an inconspicuous gestation period. As mice lacking α11β1 integrins, also tKO mice show postnatal growth retardation due to diminished insulin growth factor-1 levels, which resolves in adulthood. Histological analysis of tKO skin did not reveal striking alterations in comparison to controls. However, dermal fibroblasts, which in control mice express all three integrins, derived from tKO mice failed to adhere to and spread on collagen I, but were comparable to controls on fibronectin. Given that tKO mice display normal survival, we sought to investigate the status of non-integrin collagen receptors in these integrin-deficient mice. We observed that discoidin domain receptor 2 (DDR2), a collagen receptor of the receptor tyrosine kinase family, showed upregulated expression as well as increased kinase activity in tKO fibroblasts in response to collagen when compared to controls. This finding clearly showed that even enhanced activity of DDR2 does not rescue tKO fibroblast adhesion to collagen. Rather, DDR2 seems to fulfill signaling functions that are distinct from adhesive functions. Together, our work on integrin-deficient mice indicates that direct contact of cells with collagens is dispensable for mouse life in unchallenged conditions.