Further Development 15.18: Netrin, the Bifunctional Guidance Cue

Neural Crest Cells and Axonal Specificity

The structures of the netrin proteins have numerous regions of homology with UNC-6, a protein implicated in directing the migration of axons around the body wall of C. elegans. In the wild-type nematode, UNC-6 induces axons from certain centrally located sensory neurons to move ventrally while inducing ventrally placed motor neurons to extend axons dorsally. In unc-6 loss-of-function mutations, neither of these migrations occurs (Hedgecock et al. 1990; Ishii et al. 1992; Hamelin et al. 1993). Mutations of the unc-40 gene disrupt ventral (but not dorsal) axon migration, whereas mutations of the unc-5 gene prevent only dorsal migration (Figure 1). Genetic and biochemical evidence suggests that UNC-5 and UNC-40 are portions of the UNC-6 receptor complex, and that UNC-5 can convert a UNC-40-mediated attraction into a repulsion (Leonardo et al. 1997; Hong et al. 1999; Chang et al. 2004). Moreover, in vitro studies indicate that Shh, netrins, and other attractant molecules function through the Src family kinases (SFKs) to mediate growth cone responses (Li et al. 2004; Meriane et al. 2004; Yam et al. 2009; Ruiz de Almodovar et al. 2011). It will be exciting to see if future in vivo studies reveal possible spatiotemporal roles for SFKs in the midline crossing of commissural axons.

There is reciprocity in science. Just as research on vertebrate netrin genes led to the discovery of their C. elegans homologues, research on the nematode unc-5 gene led to the discovery of the gene encoding the mammalian netrin receptor. This gene turns out to be one whose mutation in mice causes a disease called rostral cerebellar malformation (Ackerman et al. 1997; Leonardo et al. 1997). Similarly, the netrin DCC receptor received its name from analysis of mutated genes associated with cancer and garnered its acronym from “deleted in colorectal cancer.”

**Figure 1** UNC expression and function in axonal guidance. (A) In the body of the wild-type *C. elegans* embryo, sensory neurons project ventrally, and motor neurons project dorsally. The ventral body wall epidermoblasts expressing UNC-6 are darkly shaded. (B) In the *unc-6* mutant embryo, neither of these migrations occurs. (C) The *unc-5* loss-of-function mutation affects only the dorsal movements of the motor neurons. (D) The *unc-40* loss-of-function mutation affects only the ventral migration of the sensory growth cones. (After C. S. Goodman. 1994. *Cell* 78: 353–356.)

Literature Cited

Ackerman, S. L., L. P. Kozak, S. A. Przyborski, L. A. Rund, B. B. Boyer and B. B. Knowles. 1997. The rostral malformation gene encodes an UNC-5-like protein. Nature 386: 838–842.
PubMed Link

Chang, C., T. W. Yu, C. I. Bargmann and M. Tessier-Lavigne. 2004. Inhibition of netrin-mediated axon attraction by a receptor protein tyrosine phosphatase.Science 305: 103–106.
PubMed Link

Goodman, C. S. 1994. The likeness of being: Phylogenetically conserved molecular mechanisms of growth cone guidance. Cell 78: 353–356.
PubMed Link

Hamelin, M., Y. Zhou, M.-W. Su, I. M. Scott and J. G. Culotti. 1993. Expression of the unc-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally. Nature 364: 327–330.
PubMed Link

Hedgecock, E. M., J. G. Culotti and D. H. Hall. 1990. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4: 61–85.
PubMed Link

Hong, K., L. Hinck, M. Nishiyama, M. M. Poo, M. Tessier-Lavigne and E. Stein. 1999. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97: 927–941.
PubMed Link

Ishii, N., W. G. Wadsworth, B. D. Stern, J. G. Culotti and E. M. Hedgecock. 1992. UNC-6, a laminin-related protein, guides pioneer axon migrations in C. elegans. Neuron 9: 873–881.
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Leonardo, E. D., L. Hinck, M. Masu, K. Keino-Masu, S. L. Ackerman and M. Tessier-Lavigne. 1997. Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386: 833–838.
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Li, W. and 12 others. 2004. Activation of FAK and Src are receptor-proximal events required for Netrin signaling. Nat. Neurosci. 7: 1213–1221.
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Meriane, M. and 7 others. 2004. Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance. J. Cell Biol. 167: 687–698.
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Ruiz de Almodovar, C. and 20 others. 2011. VEGF mediates commissural axon chemoattraction through its receptor Flk1. Neuron 70: 966–978.
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Yam, P. T., S. D. Langlois, S. Morin, and F. Charron. 2009. Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron 62: 349–362.
PubMed Link

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