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.”
Literature Cited
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