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

Cell. 1999 Jun 25;97(7):927-41. doi: 10.1016/s0092-8674(00)80804-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Axons / physiology*
  • Binding Sites
  • COS Cells
  • Caenorhabditis elegans Proteins*
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Cytoplasm / metabolism
  • DCC Receptor
  • Growth Cones / physiology
  • Helminth Proteins / genetics
  • Helminth Proteins / metabolism*
  • Ligands
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Molecular Sequence Data
  • Nerve Growth Factors / metabolism
  • Netrin Receptors
  • Netrin-1
  • Rats
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Growth Factor / genetics
  • Receptors, Growth Factor / metabolism*
  • Tumor Suppressor Proteins*
  • Xenopus / embryology


  • Caenorhabditis elegans Proteins
  • Cell Adhesion Molecules
  • DCC Receptor
  • Dcc protein, mouse
  • Helminth Proteins
  • Ligands
  • Membrane Proteins
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Receptors, Cell Surface
  • Receptors, Growth Factor
  • Tumor Suppressor Proteins
  • UNC-5 protein, C elegans
  • Netrin-1