Overview: Studying Integrins In Vivo

Integrins are adhesive proteins that have evolved to mediate cell–cell and cell–matrix communication that is indispensable for development and postnatal physiology. Despite their widespread expression, the genetic deletion of specific integrin family members in lower organisms as well as mammals leads to relatively distinct abnormalities. Many of the processes in which integrins participate have a requirement for strong adhesion coincident with times of mechanical stress. In Drosophila, the absence of specific integrins leads to detachment of muscle from the gut and body wall and separation of the two epithelial layers in the wing. In mice and humans, a deletion of either subunit of the laminin-binding integrin, α6β4 leads to severe skin blistering and defects in other epithelial layers. In addition, integrins have also evolved to serve more subspecialized roles ranging from the establishment of a stem cell niche in Drosophila and mammals, to the regulation of pathogenic tumor vascularization, platelet adhesion, and leukocyte transmigration in mammalian systems. However, some cells seem to function normally in the absence of all integrins, as revealed by the very surprising finding that deletion of all the major integrin types on dendritic cells of mice has no effect on the ability of these cells to migrate within the interstitium of the skin and enter into lymphatics. In addition to serving as transmembrane mechanical links, integrins in vertebrates synergize with a number of receptors including growth factor receptors, to enhance responses. This leads to the activation of a large signaling network that affects cell proliferation and differentiation, as well as cell shape and migration. In vivo studies, in lower organisms, knockout mouse models as well as in inherited human diseases together have provided important insights into how this major, primordial family of adhesion receptors have remained true to their name “integrins” as their diverse functions have in common the ability to integrate extracellular stimuli into intracellular signals that affect cell behavior.