Signaling switch of the axon guidance receptor Robo3 during vertebrate evolution

Neuron. 2014 Dec 17;84(6):1258-72. doi: 10.1016/j.neuron.2014.11.004. Epub 2014 Nov 26.


Development of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain. Instead, Netrin-1 selectively triggers phosphorylation of mammalian Robo3 via Src kinases. Robo3 does not bind Netrin-1 directly but interacts with DCC. Netrin-1 fails to attract pontine neurons lacking Robo3, and attraction can be restored in Robo3(-/-) mice by expression of mammalian, but not nonmammalian, Robo3. We propose that Robo3 evolution was key to sculpting the mammalian brain by converting a receptor for Slit repulsion into one that both silences Slit repulsion and potentiates Netrin attraction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Biological Evolution*
  • Cell Movement
  • DCC Receptor
  • Glycoproteins / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Mice
  • Nerve Growth Factors / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Netrin-1
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism
  • Zebrafish
  • src-Family Kinases / metabolism


  • DCC Receptor
  • Dcc protein, mouse
  • Glycoproteins
  • Membrane Proteins
  • NTN1 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Robo3 protein, mouse
  • Tumor Suppressor Proteins
  • slit protein, vertebrate
  • Netrin-1
  • src-Family Kinases