Regulation of axonal growth in the vertebrate nervous system by interactions between glycoproteins belonging to two subgroups of the immunoglobulin superfamily.

T H~ mechanism of formation of connections between neurons by axons and dendrites is one of the crucial and interesting aspects of neural development. To reach their intended targets, extending axons depend on a complex pattern of guidance cues present in their local environment (Dodd and Jessell, 1988). Several distinct mechanisms have been postulated for such guidance functions. (a) Neurite growth-promoting proteins exposed either at the surface of neuronal or nonneuronal cells, or localized in the extracellular matrix (ECM) ~ provide pathways along which axons can preferentially elongate (Rathjen and Jessell, 1991; Grumet, 1991; Reichardt and Tomaselli, 1991; Takeichi, 1991). (b) Repulsive molecules may block axonal extension into certain territories; e.g., by contact inhibition of the mobility of growth cones. In spatial and temporal concert with molecules favorable to axon growth, such molecules may be involved in guidance (Caroni and Schwab, 1988; Stahl et al., 1990; Raper and Kapfhammer, 1990; Keynes et al., 1991; Chiquet-Ehrismann, 1991). (c) Soluble chemoattractants, released by intermediate or final cellular targets, might guide axons by the establishment of concentration gradients (Lumsden and Davies, 1986; Tessier-Lavigne et al., 1988; Heffner et al., 1990; Placzek et al., 1990). Axon growth on favorable substrata involves specific interactions with cell surface glycoproteins. Three major structural classes of axonal membrane proteins have been described so far to undergo specific interactions with neurite growth-promoting ECM or cell surface molecules, and thus, have been implicated as axonal receptors in the growthgenerating machinery: (a) integrins of the 13~ and/33 subfamilies (Reichardt and Tomaselli, 1991), (b) cadherins (Takeichi, 1991), and (c) axonal membrane proteins of the Ig superfamily (Rathjen and Jessell, 1991; Grumet, 1991; Hortsch and Goodman, 1991). Ig-like proteins concentrated on axons can be further classified by the expression of both Igand fibronectin type III (FNIII)-related repeats (referred to as Ig/FNIII-like proteins in the following), or Ig-like domains alone. According to the overall domain organization and primary sequence, the group of Ig/FNIII-like proteins in vertebrates can be further divided into subgroups (Fig. 1).