Floor-plate-derived netrin-1 is dispensable for commissural axon guidance

Nature. 2017 May 18;545(7654):350-354. doi: 10.1038/nature22331. Epub 2017 Apr 26.

Abstract

Netrin-1 is an evolutionarily conserved, secreted extracellular matrix protein involved in axon guidance at the central nervous system midline. Netrin-1 is expressed by cells localized at the central nervous system midline, such as those of the floor plate in vertebrate embryos. Growth cone turning assays and three-dimensional gel diffusion assays have shown that netrin-1 can attract commissural axons. Loss-of-function experiments further demonstrated that commissural axon extension to the midline is severely impaired in the absence of netrin-1 (refs 3, 7, 8, 9). Together, these data have long supported a model in which commissural axons are attracted by a netrin-1 gradient diffusing from the midline. Here we selectively ablate netrin-1 expression in floor-plate cells using a Ntn1 conditional knockout mouse line. We find that hindbrain and spinal cord commissural axons develop normally in the absence of floor-plate-derived netrin-1. Furthermore, we show that netrin-1 is highly expressed by cells in the ventricular zone, which can release netrin-1 at the pial surface where it binds to commissural axons. Notably, Ntn1 deletion from the ventricular zone phenocopies commissural axon guidance defects previously described in Ntn1-knockout mice. These results show that the classical view that attraction of commissural axons is mediated by a gradient of floor-plate-derived netrin-1 is inaccurate and that netrin-1 primarily acts locally by promoting growth cone adhesion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axon Guidance*
  • Cell Adhesion
  • Female
  • Growth Cones / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Growth Factors / deficiency
  • Nerve Growth Factors / metabolism*
  • Netrin-1
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Spinal Cord / cytology*
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Tumor Suppressor Proteins
  • Netrin-1