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

Lynda Erskine, Urielle Francois, Laura Denti, Andy Joyce, Miguel Tillo, Freyja Bruce, Neil Vargesson, Christiana Ruhrberg

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)2504-2516
Number of pages13
JournalDevelopment
Volume144
Issue number13
Early online date4 Jul 2017
DOIs
Publication statusPublished - Jul 2017

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Neuropilin-1
Vascular Endothelial Growth Factor A
Blood Vessels
Axons
Neurons
Retinal Ganglion Cells
Protein Isoforms
Brain
Fasciculation
Optic Chiasm
Alleles
Growth

Keywords

  • retinal ganglion cell
  • optic chiasm
  • blood vessel
  • axon guidance
  • VEGF-A

Cite this

VEGF-A and Neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels. / Erskine, Lynda; Francois, Urielle ; Denti, Laura; Joyce, Andy; Tillo, Miguel; Bruce, Freyja; Vargesson, Neil; Ruhrberg, Christiana.

In: Development, Vol. 144, No. 13, 07.2017, p. 2504-2516.

Research output: Contribution to journalArticle

Erskine, Lynda ; Francois, Urielle ; Denti, Laura ; Joyce, Andy ; Tillo, Miguel ; Bruce, Freyja ; Vargesson, Neil ; Ruhrberg, Christiana. / VEGF-A and Neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels. In: Development. 2017 ; Vol. 144, No. 13. pp. 2504-2516.
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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.",
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note = "We thank Vann Bennett and Daizing Zhou (Department of Biochemistry, Duke University Medical Center) for the design and generation of the Brn3bCre knock-in mice. We are grateful to Bennett Alakakone and Susan Reijntjes for help with preliminary experiments and to Anastasia Lampropoulou for preparing tissue culture media. We thank the staff of the Biological Resource Unit at the UCL Institute of Ophthalmology and the University of Aberdeen Institute of Medical Sciences Microscopy and Histology Facility and Medical Research Facility for technical assistance. Funding This research was funded by project grants from the Wellcome Trust [085476/A/08/Z to L.E., C.R.] and Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J00815X/1 to L.E.; BB/J00930X/1 to C.R.] and a Wellcome Trust PhD Fellowship [092839/Z/10/Z to M.T.]. Deposited in PMC for immediate release.",
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T1 - VEGF-A and Neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels

AU - Erskine, Lynda

AU - Francois, Urielle

AU - Denti, Laura

AU - Joyce, Andy

AU - Tillo, Miguel

AU - Bruce, Freyja

AU - Vargesson, Neil

AU - Ruhrberg, Christiana

N1 - We thank Vann Bennett and Daizing Zhou (Department of Biochemistry, Duke University Medical Center) for the design and generation of the Brn3bCre knock-in mice. We are grateful to Bennett Alakakone and Susan Reijntjes for help with preliminary experiments and to Anastasia Lampropoulou for preparing tissue culture media. We thank the staff of the Biological Resource Unit at the UCL Institute of Ophthalmology and the University of Aberdeen Institute of Medical Sciences Microscopy and Histology Facility and Medical Research Facility for technical assistance. Funding This research was funded by project grants from the Wellcome Trust [085476/A/08/Z to L.E., C.R.] and Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J00815X/1 to L.E.; BB/J00930X/1 to C.R.] and a Wellcome Trust PhD Fellowship [092839/Z/10/Z to M.T.]. Deposited in PMC for immediate release.

PY - 2017/7

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N2 - 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.

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KW - retinal ganglion cell

KW - optic chiasm

KW - blood vessel

KW - axon guidance

KW - VEGF-A

U2 - 10.1242/dev.151621

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VL - 144

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JO - Development

JF - Development

SN - 0950-1991

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ER -