How do tissues connect? Elucidating a newly identified matrix adhesion system

Tissues are surrounded and usually separated by basement membranes. However, some tissues connect through adjoining basement membranes. The functional significance and mechanisms underlying these connections remain elusive due to a lack of experimental models and tools. A basement membrane linkage in the C. elegans uterus is essential for maintaining reproductive organ integrity. Using genetic manipulation and endogenous protein tagging, we discovered an adhesion complex that connects tissues through adjoining basement membranes. The components of this complex are conserved and present at basement membrane linkage sites in multiple human tissues including kidney filtration capillaries, the blood-brain barrier, lung alveoli, the cochlea and eye. Strikingly, loss of linkage components in the kidney and cochlea results in tissue/basement membrane splitting and organ dysfunction. To elucidate the structure and mechanisms underlying this novel adhesion complex we will use a platform of animal and cell systems to: 1) create an atlas of basement membrane tissue linkages; 2) determine how linkages promote tissue function and are disrupted in disease; and 3) define how defective linkages and tissue function can be restored. Resolving tissue linkage mechanisms will transform knowledge about tissue organisation and will inform strategies to protect and repair tissue connections and improve human health.