Figure 1. Diagramatic representations of the diverse structures of representative neural immunoglobulin (Ig) superfamily members. All members of the family have at least one Ig-like domain, but they also contain other domains that are represented by the symbols shown at the bottom of the figure. See the text for more information about these molecules. DCC, deleted in colorectal cancer; FGFR, fibroblast growth factor receptor; LAMP, limbic system-associated membrane protein; N-CAM, neural cell adhesion molecule; RPTP, receptor protein tyrosine phosphatase.

Figure 2. Molecular mechanisms by which homophilic interactions of immunoglobulin superfamily cell adhesion molecules (IgCAMs) induce signal transduction pathways within cells that promote neurite outgrowth. One concept, shown in green, is that neural cell adhesion molecule (N-CAM) and L1 are able to cluster with the fibroblast growth factor receptor (FGFR) and induce its autophosphorylation. This results in activation of phospholipase C (PLC), generation of diacylglycerol (DAG) and the release of arachidonic acid (AA) by DAG lipase, causing increased calcium influx. Another mechanism, shown in yellow, is that N-CAM and L1 interact with Fyn and Src tyrosine kinases, respectively, inducing a cascade that results in activation of extracellular signal-regulated kinases (ERKs). Downstream events resulting from the increased calcium concentration and ERK activation promote neurite outgrowth by mechanisms currently under investigation.

Figure 3. Locations of immunoglobulin superfamily (IgSF) members in axonal and glial membrane domains of myelinated axons. The nodal regions, which separate the segments of myelin (internodes) on myelinated axons, are divided into distinct domains with differing structures and biochemical compositions: the node itself where ion fluxes generating the action potential occur, paranodes (PN) with glial lateral loops that make tight junctions with the axonal surface membrane (axolemma), and juxtaparanodes (JPN). The internodes include the compact myelin as well as the glial membranes at the outside (abaxonal) and inside (adaxonal) of the myelin sheath. The structures of IgSF proteins, which are specifically expressed by myelin-forming glia, are shown in the box at the upper left of the figure. These proteins are selectively localized in the internode at sites shown by the arrows: protein zero (P0), compact myelin; myelin–oligodendrocyte glycoprotein (MOG), abaxonal membrane; and myelin-associated glycoprotein (MAG), adaxonal membrane. Proteins expressed specifically in axonal membranes of the JPN, PN and node are listed in the boxes at the bottom of the figure, and those in the glial membranes of the PN and JPN are in the boxes above the nodal region. IgSF members, which are shown in bold type, contribute to the formation and maintenance of these structures by interacting with other membrane or cytoskeletal proteins. The structures of these IgSF proteins or similar family members are shown in Figure 1. NF, neurofascin; OSP, oligodendrocyte-specific protein; Caspr, contactin-associated protein; Nr-CAM, neuron-gliaCAM-related CAM; TAG-1, transiently expressed axonal surface glycoprotein-1; CNS, central nervous system; PNS, peripheral nervous system.