Cell Adhesion And Labeled Pathways

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Growth cones, in addition to using ECM, make contact with the membranes of other cells and axons. In this, they are supported by a set of cell adhesion molecules (CAMs) (Walsh and Doherty, 1997). There are a host of such molecules, and they come in several classes (Figure 5.19). The most prominent class is the IgG superfamily. Members of this class have extracellular repeat domains similar to those found in antibodies, reflecting perhaps an ancient adhesive function for the IgG superfamily. Another class is the calcium-dependent cadherins. One property that many CAMs share is their ability to bind homophilically. Homophilic binding means that proteins of the same type bind to each other. Thus, if two cells express the same homophilic CAM on their surfaces, the CAM on the one cell will act as receptor for the CAM on the

Fasciclin II axons and growth cones

Fasciclin II axons and growth cones

FIGURE 5.21 A homophilic mutant in flies. A. In normal Drosophila embryos, DMP2, MP1, vMP2, and pCC axons fasciculate in a longitudinal bundle in which all axons express fasll. B. In a fasII mutant, these axons do not fasciculate normally. (After Grenningloh et al., 1991)

other cell and vice versa, causing the two cells to adhere to each other. To test whether a particular CAM is homophilic, nonadherent cells are transfected with the CAM and assayed with respect to whether they then form aggregates. During outgrowth, axons expressing the same CAMs often fasciculate with one another. Thus, single pioneer axons may use a specific CAM to guide the follower axons that express the same CAM, and these axons can attract the fascicula-tion of still later axons of the same type. In this way, pioneer axons can become the founders for large axonal tracts within the CNS.

Monoclonal antibodies raised against axonal membranes have been used to search for cell adhesion molecules that are expressed on particular fascicles of fibers during neural pathway formation. Several molecules were discovered in this manner. Some CAMs show a particularly restricted expression and result in very specific defects in axon growth. For example, a Drosophila CAM, called fasciclinll (FasII), is expressed on a subset of longitudinal tracts or fascicles in the CNS (Bastiani et al., 1987). In FasII mutants, axons that normally express this gene defasciculate, and the longitudinal tracts in which they run become disorganized (Grenningloh et al., 1991) (Figure 5.21). When FasII is transgenically misexpressed on CNS neurons that would not normally express FasII, their axons tend to join together abnormally. Another CAM in Drosophila, called IrreC, is expressed in the optic lobes, and IrreC mutants show specific miswiring of the optic pathway (Ramos et al., 1993). The vertebrate homolog of IrreC has been implicated in the formation of

Neuron specific tracts in the spinal cord and cerebellum. In mammals, limbic-associated membrane protein, LAMP, is an IgCAM expressed by neurons throughout the limbic system, a cortical and subcortical area of the brain that functions in emotion and memory (Horton and Levitt, 1988). Administration of LAMP antibodies to developing mouse brains results in abnormal growth of the fiber projections in the limbic system, suggesting that LAMP is an essential recognition molecule for the formation of limbic connections (Pimenta et al., 1995). LAMP has three IgG domains, and these domains appear to participate in different ways to enhance local wiring. LAMP enhances neurite outgrowth through homophilic interactions with other neurons in the limbic circuit using the first of its IgG domains, but inhibits neurite outgrowth of non-LAMP-expressing neurons using heterophilic interactions involving the second IgG domain (Eagleson et al., 2003). The function of the third domain is not known.

Neural cell adhesion molecule (NCAM), the earliest identified of the CAMs, appears to be expressed on all vertebrate neurons and glia (Edelman, 1984). NCAM exists in many different forms, some with an intracel-lular domain that may interact with the cytoskeleton and some without. The extracellular portion of NCAM can be highly modified by the addition of carbohydrates, particularly sialic acid residues. Nonsialylated forms are very adhesive compared to the sialylated forms. In the course of a neuron's development, there may be changes in the sialylation state of its NCAM, thus adjusting its adhesion (Walsh and Doherty, 1997). For example, developing motor neurons of the chick grow out of the spinal cord and enter a complicated plexus region, where they cross in many directions and eventually segregate into distinct nerve roots leading to their appropriate muscles. During the time when these axons are growing in the plexus, the NCAM they express is highly sialylated. This keeps the axons that are headed toward different muscles from fasciculat-ing indiscriminately with one another. If the sialic acid is digested away with endoneuraminidase (Endo-N), errors in pathfinding occur in the plexus region, and motor axons exit into the wrong peripheral nerves (Tang et al., 1994) (Figure 5.22).

Growing axons respond to a variety of cues as they navigate, so the loss of just one of these may affect axon growth and navigation in a limited way. In many gene deletion studies in Drosophila, there is a significant increase in pathfinding errors, but the majority of axons usually grow along the correct pathway. For instance, in fasII mutants mentioned above, although longitudinal tracts are somewhat defasciculated, the axons are still able to grow in the correct directions. In some CAM knockouts, for instance the NCAM knock

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