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Riddle DL, Blumenthal T, Meyer BJ, et al., editors. C. elegans II. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.

Cover of C. elegans II

C. elegans II. 2nd edition.

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Section IIINetrins Guide Circumferential Migrations

Three known genes, unc-5 , unc-6 , and unc-40 , are required to guide the circumferential migrations of neuronal growth cones and mesoblasts on the body wall (Hedgecock et al. 1990). unc-6 is required for guiding both dorsal and ventral migrations, whereas unc-5 is required only for dorsal migrations. unc-40 is required for most or all unc-6 functions; existing alleles of unc-40 severely disrupt ventral migrations but also weakly affect dorsal migrations. Unlike unc-5 and unc-6 , mutations in unc-40 also affect hypodermal cell intercalations and Q neuroblast migrations.

UNC-6 is a laminin-related protein with a unique carboxyl terminus (Fig. 5) (Ishii et al. 1992). Recently, vertebrate orthologs, called netrins, have been isolated as growth cone chemoattractants expressed in the floorplate of the developing spinal cord (Kennedy et al. 1994; Serafini et al. 1994). UNC-6 is expressed by 12 types of hypodermoblasts, sheaths, and neurons of ectodermal origin during embryonic or larval development in the hermaphrodite (Wadsworth et al. 1996). Like the vertebrate netrins (Kennedy et al. 1994), UNC-6 expression is restricted to the ventralmost cells within each region of the nervous system (see Fig. 3). A simple model is that netrin gradients on neuroepithelia, peaking along the ventral midline, act as attractive or repulsive cues, respectively, for ventral and dorsal migrations (Colamarino and Tessier-Lavigne 1995; Wadsworth et al. 1996). Whether netrin is attractive or repulsive evidently depends on the motile cell itself and, particularly, on the current state of its navigational program.

Figure 5. One-dimensional representations of C.

Figure 5

One-dimensional representations of C. elegans gene products involved in cell and growth cone migrations. The modular organization of domains I–VI of mouse laminin γ is shown for comparison (more...)

The domain structure of netrins, which is conserved from nematodes to chordates, has several implications for their biological activities. The amino terminus is homologous to domains VI and V of laminin subunits α, β, and γ (Fig. 5). Laminin molecules, which are heterotrimers of all three subunits, self-assemble via their domain VI, forming a stable, polymeric scaffold for the basal lamina (Yurchenco and Cheng 1993). Thus, netrin domain VI could allow its incorporation into basal laminae by copolymerization with laminin. Several epidermal growth factor (EGF)-like modules in domains V and III of laminin subunits are proposed to form binding sites for integrins and other cellular receptors (Beck et al. 1990; Hynes and Lander 1992). By inference, netrin modules V-1, V-2, or V-3 might be the ligands for receptors on growth cones and migrating cells that respond to netrin cues. Finally, the basic domain at the carboxyl terminus could tether netrin to other molecules for display on cell surfaces or unique matrix sites.

Molecular analysis of selective loss-of-function and null alleles of unc-6 indicates that the biological activities of netrins are mediated through distinct protein domains (Wadsworth et al. 1996). Inframe deletions of the EGF-like module V-2 disrupt netrin-mediated repulsion but not attraction (Fig. 5). This module could provide a binding site for the repulsion receptor UNC-5 (discussed below). Missense and other subtle mutations in domain VI can produce other selective loss-of-function phenotypes. A mutation near the end of domain VI selectively disrupts mesoblast but not axonal migrations. Conceivably, this mutation could affect the display of UNC-6 on the outward face of basal laminae that contacts mesoblasts but not its display on the inward face or cell surfaces that contact neuronal growth cones. A mutation nearer the middle of domain VI selectively disrupts ventral migrations of both axons and mesoblasts. One possibility is that the receptor mediating attraction binds to this module. Alternatively, some distinct mechanism of tethering, affected by this mutation, may be used to maintain a high concentration of netrin along the ventral midline. Finally, deletions of the 3′exons coding for module V-3 and domain C result in a null phenotype.

UNC-5 is a novel cell surface receptor with an extracellular amino terminus comprising two immunoglobulin and two thrombospondin type I modules (T1 in Fig. 5) and a large intracellular carboxyl terminus including a potential SH3 module (SH in Fig. 5) (Leung-Hagesteijn et al. 1992). UNC-5 expression on the surface of motile cells appears both necessary and sufficient to orient them away from UNC-6 sources (Hamelin et al. 1993; M. Su et al., in prep.). UNC-40 is a cell surface protein with an extracellular amino terminus comprising four immunoglobulin and six fibronectin III modules and a large intracellular carboxyl terminus (Fig. 5) (S. Chan et al., in prep.).

UNC-40 is closely related to DCC (Chan et al. 1996), a protein frequently inactivated in human colorectal cancer (Hedrick et al. 1994). DCC and its orthologs in other vertebrates are expressed in developing epithelia and in neurons undergoing axonogenesis (Lawlor and Narayanan 1992; Chuong et al. 1994; Pierceall et al. 1994a,b; Vielmetter et al. 1994). UNC-40 is apparently expressed in all of the neurons and mesoblasts that are known to undergo netrin-guided movements (S. Chan et al., in prep.). Interestingly, certain neurons that grow strictly along the ventral midline also express this receptor; netrin attraction may help prevent these growth cones from straying from the midline as they migrate longitudinally along the ventral hypodermis (Hedgecock et al. 1990; Wadsworth et al. 1996). In contrast to UNC-5, it is not yet known whether UNC-40 has an instructive role in netrin-guided movements. It evidently acts with UNC-5 to orient motile cells away from netrin sources; it may act either alone or with some unknown instructive partner to orient motile cells toward netrin sources. Vertebrate netrins may interact directly with DCC (Keino-Masu et al. 1996). The various netrin-independent phenotypes of unc-40 mutants suggest that UNC-40/DCC have a widespread role in cell adhesion and motility.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
Bookshelf ID: NBK20137
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