4.7 Article

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

Journal

DEVELOPMENT
Volume 144, Issue 13, Pages 2504-2516

Publisher

COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.151621

Keywords

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

Funding

  1. Wellcome Trust [085476/A/08/Z]
  2. Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J00815X/1, BB/J00930X/1]
  3. Wellcome Trust PhD Fellowship [092839/Z/10/Z]
  4. Wellcome Trust [092839/Z/10/Z, 085476/A/08/Z] Funding Source: Wellcome Trust
  5. BBSRC [BB/J00930X/1, BB/J00815X/1] Funding Source: UKRI
  6. Biotechnology and Biological Sciences Research Council [BB/J00930X/1, BB/J00815X/1] Funding Source: researchfish

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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 Brn3b(Cre) 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 Vegfa(120/120) and Vegfa(188/188) mice, which have vascular defects as a result of their expression of single VEGF-A isoforms. Ectopic midline vascularisation in endothelial Nrp1 and Vegfa(188/188) 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.

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