Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2

Science. 2015 Nov 20;350(6263):961-5. doi: 10.1126/science.aad2615.

Abstract

Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2-mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)-mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / physiology*
  • Ligands
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Nerve Growth Factors / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Netrin-1
  • Neurogenesis / genetics
  • Neurogenesis / physiology*
  • Receptors, Cell Surface
  • Receptors, Immunologic / metabolism
  • Spinal Cord / embryology*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Ligands
  • Membrane Proteins
  • Nell2 protein, mouse
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Robo2 protein, mouse
  • Robo3 protein, mouse
  • Slit1 protein, mouse
  • Tumor Suppressor Proteins
  • roundabout protein
  • Netrin-1