A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion

Netrins are bifunctional: they attract some axons and repel others. Netrin receptors of the Deleted in Colorectal Cancer (DCC) family are implicated i n attraction and those of the UNC5 family in repulsion, but genetic evidenc e also suggests involvement of the DCC protein UNC-40 in some cases of repu lsion. 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. Vie show that attraction is converted to repulsi on by expression of UNC5 proteins in these cells, that this repulsion requi res 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 protei ns interact directly, but this interaction is repressed in the context of t he full-length proteins. We provide evidence that netrin-1 triggers the for mation of a receptor complex of DCC: and UNC5 proteins and simultaneously d erepresses the interaction between their cytoplasmic domains, thereby conve rting DCC-mediated attraction to UNC5/DCC-mediated repulsion.