Trends in Neurosciences
Volume 25, Issue 8, 1 August 2002, Pages 423-429
Journal home page for Trends in Neurosciences

Review
Moving around in a worm: netrin UNC-6 and circumferential axon guidance in C. elegans

https://doi.org/10.1016/S0166-2236(02)02206-3Get rights and content

Abstract

How does an extracellular guidance molecule direct multiple growth cones to different positions? The answer is important for understanding the development of complex neural connections. UNC-6 is a member of the netrin family of guidance proteins. It has phylogenetically conserved domains that mediate its different guidance and branching activities. In the Caenorhabditis elegans embryo, UNC-6 is secreted ventrally and a pattern of circumferential axon tracts develops as pioneer growth cones bearing UNC-5 and UNC-40 receptors are directed towards, or away from, the ventral sources. Following the first migrations, UNC-6 from additional sources allows more complex migration patterns to emerge. In addition, at specific dorsoventral positions, locally restricted extracellular molecules alter growth cone responses to UNC-6, causing circumferentially migrating growth cones to turn and longitudinal nerves to develop. These observations show that extracellular guidance molecules can direct complex arrangements of migrating growth cones in vivo by eliciting different types of responses, by spatially and temporally regulating their expression and by working in concert with other extracellular molecules.

Section snippets

UNC-6

Like most extracellular matrix and cell adhesion molecules, the UNC-6/netrin comprises multiple domains that are found in functionally divergent proteins. The UNC-6 VI and V domains are similar to the N-termini of subunits of laminin, which are phylogenetically conserved glycoprotein components of basement membranes [1]. The UNC-6 C domain is also conserved: it has been found in the complement C345 protein family, frizzled-related proteins, type-I-C-proteinase enhancer proteins (PCOLCE) and

Developing axon tracts

The patterning of axon tracts begins as neuronal growth cones from pioneer neurons are guided across the basal surface of the ectoderm. The expression of unc-6 by a set of epidermal cells precedes the first migrations [5]. Expression in these cells begins just before they form two symmetric rows on either side of the embryo. Expression continues as these cells slide over the neuroectoderm, and ends shortly after the cells meet at the ventral midline. At the end of this process, the neuroblasts

Dorsoventral positioning

Longitudinal nerves form at stereotyped dorsoventral positions as circumferentially migrating axons reach a position and turn in the longitudinal direction. Several observations suggest that the UNC-6 circumferential-guidance system can function independently of the system that guides longitudinal axon migration, and that a migrating axon is capable of responding to both systems. First, in unc-6 mutants, circumferential but not longitudinal migrations are disrupted [4]. Further, ectopic

Crossing the ventral midline

At the ventral midline, some axons cross and then turn longitudinally to make connections with axon tracts that develop on the other side of the body. The ventral nerve cord has two fascicles that flank the ventral midline (Fig. 4a). These axon tracts both run along an interface between the ventral epidermis and the ventral margin of the ventral sublateral muscle cells. Again, the dorsoventral position of these tracts appears to be determined by the combination of guidance molecules axons

Conclusions

In the nervous system, an intricate network of connections is made between neurons. These connections emerge as neuronal growth cones are directed through their environment by extracellular guidance molecules. Recent studies have implicated molecules as guidance cues or as receptors for such cues. In addition, some of the cytoplasmic signal transduction that underlies responses to these cues has also been revealed. Another achievement has been to understand better the manner by which guidance

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