Extracellular matrix regulation of epithelial behaviour in morphogenesis

The substratum for many cell types is the extracellular matrix (ECM). However, the ECM is not only a physical supporting framework for the cells, but may be linked to the cells by molecules which are intimately associated with the plasma membrane. Changes in cell-ECM interactions modify cell shape, motility, and proliferation and, because the ECM distributes over many cells, can integrate these cellular events into outcomes at the tissue level. Our work on the mechanisms by which mesenchymal tissues direct the generation of epithelial organ form is based on the idea that the interacting tissues reciprocally modify the other's cell-ECM associations. Epithelia of organs such as the lung, submandibular and mammary glands begin as buds which then, under the influence of their associated mesenchymal tissue, fold to form lobules and ultimately ducts and acini. Between these tissues is a basement membrane, an ECM consisting of an epithelially-derived basal lamina and a mesenchymally-derived reticular lamina. The basal lamina, a thin, organized complex of principally type IV collagen, laminin, and proteoglycan, acts as the epithelial cell substratum. The reticular lamina, an adjacent, thick, fibrillar layer containing primarily types I, III, and V collagen and fibronectin, provides support for the basal lamina. These materials modify epithelial cell behavior in vitro: isolated basal laminae (or purified constituents) promote cell attachment and proliferation, and, type I collagen fibrils organize cells into structures resembling ducts and acini. We have used mouse embryo submandibular glands and NMuMG mammary epithelial cells to examine the role of the ECM in morphogenetic tissue interactions. Work on the submandibular gland showed that the basal lamina maintains epithelial morphology, but that the mesenchyme is required for changes in this morphology and led to the proposal that the mesenchyme dictates changes in epithelial morphology by remodeling the basement membrane. Basement membrane materials are distributed non-uniformly on the developing epithelium; a well-defined basal lamina surrounds the pre-lobular bud but reticular lamina components are only on its stalk. These distributions change with the formation of clefts and lobules; the basal lamina becomes incomplete on the lobules, the sites of rapid proliferation and collagen fibrils accumulate within the clefts, the sites of morphologic stability. These changes correlate with the turnover rates of basal lamina glycosaminoglycans (GAG). GAG (chondroitin sulfate and hyaluronate) is lost from the lobules because its rate of degradation is greater than its rate of replacement, while other GAG (notably heparan sulfate) accumulates within …