VEGF-A and neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels

Development. 2017 Jul 1;144(13):2504-2516. doi: 10.1242/dev.151621.

Abstract

Visual information is relayed from the eye to the brain via retinal ganglion cell (RGC) axons. Mice lacking NRP1 or NRP1-binding VEGF-A isoforms have defective RGC axon organisation alongside brain vascular defects. It is not known whether axonal defects are caused exclusively by defective VEGF-A signalling in RGCs or are exacerbated by abnormal vascular morphology. Targeted NRP1 ablation in RGCs with a Brn3bCre knock-in allele reduced axonal midline crossing at the optic chiasm and optic tract fasciculation. In contrast, Tie2-Cre-mediated endothelial NRP1 ablation induced axon exclusion zones in the optic tracts without impairing axon crossing. Similar defects were observed in Vegfa120/120 and Vegfa188/188 mice, which have vascular defects as a result of their expression of single VEGF-A isoforms. Ectopic midline vascularisation in endothelial Nrp1 and Vegfa188/188 mutants caused additional axonal exclusion zones within the chiasm. As in vitro and in vivo assays demonstrated that vessels do not repel axons, abnormally large or ectopically positioned vessels are likely to present physical obstacles to axon growth. We conclude that proper axonal wiring during brain development depends on the precise molecular control of neurovascular co-patterning.

Keywords: Axon guidance; Blood vessel; Neuropilin; Optic chiasm; Retinal ganglion cell; VEGF-A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Blood Vessels / embryology*
  • Blood Vessels / metabolism*
  • Body Patterning
  • Central Nervous System / embryology*
  • Central Nervous System / metabolism*
  • Diencephalon / embryology
  • Diencephalon / metabolism
  • Endothelial Cells / metabolism
  • Gene Knockdown Techniques
  • Homeodomain Proteins / metabolism
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Neovascularization, Physiologic
  • Neuropilin-1 / metabolism*
  • Optic Chiasm / embryology
  • Optic Chiasm / metabolism
  • Retinal Ganglion Cells / metabolism
  • Transcription Factor Brn-3B / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • Visual Pathways / metabolism

Substances

  • Homeodomain Proteins
  • Pou4f2 protein, mouse
  • Transcription Factor Brn-3B
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1