Regulation of development and differentiation by the extracellular matrix.

Differentiation is a continuously regulated process and interactions between the cell and its environment play a major role in maintaining stable expression of differentiation-specific genes (Blau and Baltimore, 1991). An important component of the cellular environment is the extracellular matrix (ECM), which is composed of glycoproteins, proteoglycans and glycosaminoglycans that are secreted and assembled locally into an organised network to which cells adhere (Hay, 1981). An ECM is present within mammalian embryos from the two-cell stage and is a component of the environment of all cell types, although the composition of the ECM and the spatial relationships between cells and ECM differ between tissues. Cells may be completely surrounded by ECM, as is the case for chondrocytes, or may contact the ECM only at one surface, as exemplified by epithelial and endothelial cells. In some tissues only a proportion of the cells are exposed to ECM: for example, in stratified epithelia. The ECM offers structural support for cells, and can also act as a physical barrier or selective filter to soluble molecules. It has been clear for many years (Grobstein, 1954; Bissell et al., 1982) that the ECM plays a role in regulating the differentiated phenotype of cells (reviewed by Watt, 1986), but the mechanisms involved remained largely mysterious until recently, when cell-binding sites within individual ECM glycoproteins and specific ECM receptors were identified. The cell-binding sites were mapped by using proteolytic fragments and synthetic peptides to define the minimal sequences responsible for adhesive activity. In the case of fibronectin, the primary determinant of cell-binding activity for many cell types resides in the sequence GRGDSP, which occurs in one of the type III repeats that form the central domain of the molecule (Ruoslahti and Pierschbacher, 1987). Subsequently, RGD-containing sequences have been found in other matrix proteins, and additional short linear adhesive sequence motifs have been defined, although it is clear that the three-dimensional structure of matrix proteins is also an important determinant of adhesive activity (reviewed by Humphries, 1990). Affinity chromatography techniques, together with adhesion-perturbing antibodies that recognise specific plasma membrane glycoproteins, allowed the identification of ECM receptors, many of which belong to the integrin family of α/β heterodimers (Ruoslahti and Pierschbacher, 1987; Hynes, 1987). In this review, we will summarise some of the evidence that ECM components regulate differentiation and development, describe the regulatory mechanisms involved and, finally, discuss the intracellular events that may transduce signals between ECM receptors and the nucleus.