New concepts in basement membrane biology

<jats:p>Basement membranes (BMs) are thin sheets of extracellular matrix that outline epithelia, muscle fibers, blood vessels and peripheral nerves. The current view of BM structure and functions is based mainly on transmission electron microscopy imaging, <jats:italic>in vitro</jats:italic> protein binding assays, and phenotype analysis of human patients, mutant mice and invertebrata. Recently, <jats:styled-content style="fixed-case">MS</jats:styled-content>‐based protein analysis, biomechanical testing and cell adhesion assays with <jats:italic>in vivo</jats:italic> derived <jats:styled-content style="fixed-case">BM</jats:styled-content>s have led to new and unexpected insights. Proteomic analysis combined with ultrastructural studies showed that many <jats:styled-content style="fixed-case">BM</jats:styled-content>s undergo compositional and structural changes with advancing age. Atomic force microscopy measurements in combination with phenotype analysis have revealed an altered mechanical stiffness that correlates with specific <jats:styled-content style="fixed-case">BM</jats:styled-content> pathologies in mutant mice and human patients. Atomic force microscopy‐based height measurements strongly suggest that <jats:styled-content style="fixed-case">BM</jats:styled-content>s are more than two‐fold thicker than previously estimated, providing greater freedom for modelling the large protein polymers within <jats:styled-content style="fixed-case">BM</jats:styled-content>s. In addition, data gathered using <jats:styled-content style="fixed-case">BM</jats:styled-content>s extracted from mutant mice showed that laminin has a crucial role in <jats:styled-content style="fixed-case">BM</jats:styled-content> stability. Finally, recent evidence demonstrate that <jats:styled-content style="fixed-case">BM</jats:styled-content>s are bi‐functionally organized, leading to the proposition that <jats:styled-content style="fixed-case">BM</jats:styled-content>‐sidedness contributes to the alternating epithelial and stromal tissue arrangements that are found in all metazoan species. We propose that <jats:styled-content style="fixed-case">BM</jats:styled-content>s are ancient structures with tissue‐organizing functions and were essential in the evolution of metazoan species.</jats:p>