Effects of cell adhesion molecules and extracellular matrix molecules on growth cone motility and pathfinding

During development, neurons establish synaptic connections in a precise and specific manner. In many cases, axons must traverse long distances through a complex environment comprised of a variety of cell types before reaching their target tissues. During this outgrowth period, the terminal region of the axon possesses a membranous structure called a growth cone. The growth cone is highly motile, and acts as a sensory organ that interacts with other cells and molecules in its environment. A variety of cell adhesion molecules (CAMs) and extracellular matrix (ECM) molecules are encountered during this outgrowth period. Growth cones express receptors for many of these molecules on their surface, and thus may receive instructive influences from contact with certain CAMs and ECM molecules during growth toward their target tissues.;In order to gain an understanding of how CAMs and ECM molecules influence growth cone pathfinding, several in vitro experiments were performed. The first group of experiments examined the ability of several substrate-bound CAMs and ECM to affect multiple growth parameters such as growth cone adhesivity and choices neurites make when presented with two substrates. The results of these experiments showed that substrate adhesivity did not correlate with growth rates, degree of neurite fasciculation, or substrate preference. Therefore, substrate adhesivity is not a principal factor in axonal pathfinding.;A second group of experiments utilized timelapse videomicroscopy to examine behavioral and morphological changes in growth cones upon encountering sharp borders between substrates. The results of these experiments showed that growth cone morphology is actively affected by the substrate. In addition, a large percentage of growth cones collapsed upon contact with a new substrate, indicating that collapse may be a normal response to molecules in the growth environment that are of a non-inhibitory nature. These results suggested that growth cone interactions with CAMs and ECM molecules may result in the generation of distinct intracellular signals that mediate different behavioral responses of the growth cone.;A third set of experiments examined the distribution of cytoskeletal elements in growth cones growing on different CAM or ECM substrates. These experiments showed that cytoskeletal elements are distributed in unique patterns dependent upon the growth substrate. In growth cones interacting with a border between two substrates, the cytoskeletal elements underwent a progressive transition to a distribution pattern appropriate for the new substrate. These results suggest that CAMs and ECM molecules may have direct effects on the cytoskeleton of growth cones that underlie the morphological changes observed with timelapse videomicroscopy.;Together, the results described here provide new information about how growth cone motility is affected by CAMs and ECM molecules. In addition, these results suggest an interaction between CAM and ECM receptors and the underlying cytoskeleton. Therefore, although CAMs and ECM molecules function as permissive highways for axonal growth, they may also provide instructive information that is interpreted by individual growth cones and utilized for directed growth in vivo.