Epithelial mesenchymal interactions, the ECM and limb development

It has been long since recognized that cellular interactions are not always direct, i.e. they do not always take place between cells contacting each other, or between cells that emit soluble factors and other cells, which respond to it. In contrast, cross-talk between cells is frequently based on signals attached to the extracellular matrix (ECM). Thus besides proximate cell-to-cell contact, certain interactions are mediated by the ECM in a sequence: cell-to-matrix, matrix-to-cell. ECM-mediated interactions may take place within a group or sheet of cells or across adjacent cell sheets. A modified mat-like ECM, the basement membrane, separates adjacent cell sheets and mediates their interactions. Since cell sheets separated by basement membranes are an elementary feature of metazoan histology, interactions with the basement membrane have considerable importance. Recently accumulated evidence emphasizes the importance of ECM-mediated interactions. It is becoming increasingly evident that the ECM functions not only as an architectural component, but it is involved also in signal transduction. This evidence derives from four main sources: from the structure of receptor-ligand complexes, from Drosophila and C elegans genetics, from cell biological observations and from the analysis of mammalian development. In this review, I will touch upon recent evidence, illustrated by examples of FGF signalling in vertebrate limb development. Although the involvement of matrix components is not yet proven for all cases directly, the strength of multiple indications suggests that a better understanding of ECM-mediated interactions will shed new light on cell differentiation.