31 Extracellular Matrix in the Developing Nervous System

Extracellular matrix (ECM), in its broadest definition, refers to all the molecules that are inunobilized in the spaces between cells. The most extensively studiedECMs are those found in connective tissues, such as bone, cartilage, tendons, ligaments, fascia, and the stromal components of organs. Connective tissues are typically cell-poor, i.e., the ECM comprises a major fraction of the tissue mass. Accordingly, connective tissue ECMs are comparatively easy to isolate in large quantities, pennitting direct biochemical analysis. In contrast, the ECMs of nonconnective tissues are difficult or in some cases impossible (so far) to isolate, and usually must be studied by more indirect means. For this reason most progress toward an understanding of nonconnective tissue ECMs has been made only in the last 15-20 years. Under the circumstances, it is not surprising that most generalizations that have been made about how ECMs are organized and how they function have been drawn from work on connective tissues, and are not necessarily applicable to the ECMs of nonconnective tissues. Nowhere is this fact more evident than when considering the ECM of the central nervous system (CNS). For example, it is traditional to think of ECMs as consisting largely of structural molecules, such as collagens and elastin, that confer bulk tissue properties such as resistance to stress, rigidity, elasticity, or compressibility. The CNS, however, is virtually devoid of these molecules (except in association with meninges and blood vessels), a fact that explains its jellylike consistency. Moreover, while it is traditional to expect ECMs to take up certain light-microscopic stains and to exhibit certain ultrastructural features (fibrils, electrondense material), the ECM Of the CNS shows virtually none of these characteristics. Indeed, were it not for the fact that the presence of many known ECM molecules can be readily demonstrated in the brain, there would be serious debate as to whether an ECM existed there at all (as, in fact, there was for many years). Yet the existence of an ECM in the brain underscores the fact that ECMs must have functions beyond the structural and mechanical roles envisaged for them in connective tissues. Indeed, the explosion of research in the ECM field over the past 15 years has focused largely on the nonstructural properties ofECM molecules. The picture that has emerged (and is still changing) is of the ECM as a key regulator of virtually all aspects of cell behavior, including cell proliferation, shape, motility, cell-cell interactions, growth factor responses, even gene expression. During embryonic development, the ECM is uniquely suited, by virture of its immobility, to being a repository of morphogenetic information, such as the information that guides growing axons to their targets. During carcinogenesis, the ECM is ideally suited to regulate growth, differentiation, invasion, and metastasis. Most of this new information aboutECMs is being pieced together from studies of many types of cells, normal and transformed, in vivo and in vitro. Although cells of the nervous system have played an important role in this work, some of what is said in this chapter has had to be extrapolated from work on non neural tissues. Clearly, our current knowledge of the ECM of the nervous system and its functions is at a very early stage, and much new infonnation will undoubtedly be obtained in the next several years. Nevertheless, there is enough information now to conclude that the ECM plays a critical role in the formation of the nervous system, and its response to injury.