RETRACTED: A Ligand-Gated Association between Cytoplasmic Domains of UNC5 and DCC Family Receptors Converts Netrin-Induced Growth Cone Attraction to Repulsion

Abstract

Netrins are bifunctional: they attract some axons and repel others. Netrin receptors of the Deleted in Colorectal Cancer (DCC) family are implicated in attraction and those of the UNC5 family in repulsion, but genetic evidence also suggests involvement of the DCC protein UNC-40 in some cases of repulsion. To test whether these proteins form a receptor complex for repulsion, we studied the attractive responses of Xenopus spinal axons to netrin-1, which are mediated by DCC. We show that attraction is converted to repulsion by expression of UNC5 proteins in these cells, that this repulsion requires DCC function, that the UNC5 cytoplasmic domain is sufficient to effect the conversion, and that repulsion can be initiated by netrin-1 binding to either UNC5 or DCC. The isolated cytoplasmic domains of DCC and UNC5 proteins interact directly, but this interaction is repressed in the context of the full-length proteins. We provide evidence that netrin-1 triggers the formation of a receptor complex of DCC and UNC5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting DCC-mediated attraction to UNC5/DCC-mediated repulsion.

Axon guidance at the midline choice point

“…Importantly, the repulsive response of UNC-5-expressing axons was eliminated in the presence of a function-blocking antibody against DCC (Hong et al, 1999). It was further demonstrated that a ligand-induced interaction between the cytoplasmic domains of UNC-5 and DCC underlies the conversion of Netrin-1-induced attraction into repulsion (Hong et al, 1999). These findings suggest that UNC-5 proteins play an evolutionarily-conserved role in mediating repulsive events that require DCC.…”

“…In one set of experiments, the turning assay described above was used to show that exogenous expression of UNC-5 in Xenopus spinal neurons converts the attractive response of their axons/growth cones to Netrin-1 into a repulsive response (Hong et al, 1999). Importantly, the repulsive response of UNC-5-expressing axons was eliminated in the presence of a function-blocking antibody against DCC (Hong et al, 1999).…”

“…In one set of experiments, the turning assay described above was used to show that exogenous expression of UNC-5 in Xenopus spinal neurons converts the attractive response of their axons/growth cones to Netrin-1 into a repulsive response (Hong et al, 1999). Importantly, the repulsive response of UNC-5-expressing axons was eliminated in the presence of a function-blocking antibody against DCC (Hong et al, 1999). It was further demonstrated that a ligand-induced interaction between the cytoplasmic domains of UNC-5 and DCC underlies the conversion of Netrin-1-induced attraction into repulsion (Hong et al, 1999).…”

“…These findings suggest that UNC-5 proteins play an evolutionarily-conserved role in mediating repulsive events that require DCC. Interestingly, when a chimeric receptor consisting of the ectodomain of DCC and the cytoplasmic domain of UNC-5 was expressed in the Xenopus neurons, the corresponding growth cones also exhibited a repulsive response to Netrin-1 (Hong et al, 1999). Thus, repulsion appears to be encoded in the cytoplasmic domain of UNC-5.…”

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“…Four homologs of UNC5 have been described in mammals (UNC5H1, 2, 3 and 4 in rodents and UNC5A, B, C and D in humans) (Leonardo et al, 1997). Although DCC alone is implicated in the chemoattractive effect of netrin-1, it has been proposed that UNC5, associated with DCCs through their intracellular domains, is responsible for the repulsive effect of netrin-1 (Hong et al, 1999). Besides this role, UNC5 receptors are now known to have critical roles in other cellular processes, such as neuronal migration (Mehlen and Furne, 2005) and embryonic angiogenesis (Lu et al, 2004).…”