VEGF Mediates Commissural Axon Chemoattraction through Its Receptor Flk1

Abstract

Growing axons are guided to their targets by attractive and repulsive cues. In the developing spinal cord, Netrin-1 and Shh guide commissural axons towards the midline. However, the combined inhibition of their activity in commissural axon turning assays does not completely abrogate turning towards floor plate tissue, suggesting that additional guidance cues are present. Here, we show that the prototypic angiogenic factor VEGF is secreted by the floor plate and is a chemoattractant for commissural axons in vitro and in vivo. Inactivation of Vegf in the floor plate or of its receptor Flk1 in commissural neurons causes axon guidance defects, while Flk1-blockade inhibits turning of axons to VEGF in vitro. Similar to Shh and Netrin-1, VEGF-mediated commissural axon guidance requires the activity of Src family kinases. Our results identify VEGF and Flk1 as a novel ligand / receptor pair controlling commissural axon guidance.

Diverse roles for VEGF-A in the nervous system

“…VEGF-A also promotes midline crossing of axons in the spinal cord (Fig. 3D) (Ruiz de Almodovar et al, 2011). Both studies combined genetic and explant experiments to demonstrate that VEGF-A promotes axon guidance independently of its vascular roles.…”

“…The first physiological evidence that VEGF-A directly guides CNS axons in vivo was provided by two recent studies on commissural axon (see Glossary, Box 1) guidance in the mouse (Erskine et al, 2011;Ruiz de Almodovar et al, 2011). Thus, VEGF-A helps RGC axons destined for the opposite brain hemisphere to migrate through the optic chiasm, which is the diencephalic midline structure where the optic nerves from both eyes partially cross (Fig.…”

“…Both studies combined genetic and explant experiments to demonstrate that VEGF-A promotes axon guidance independently of its vascular roles. Even though VEGF-A acts through VEGFR2 on spinal commissural axons (Ruiz de Almodovar et al, 2011), it requires NRP1 to guide contralateral RGC axons (Erskine et al, 2011). The observation that embryonic RGC axons use NRP1 was surprising, as in vitro studies suggested that VEGFR2 is important for the regeneration of postnatal RGC neurons after axotomy (Bocker-Meffert et al, 2002).…”

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature

“…We showed previously that K/BxN serum-transferred arthritis induces and depends on a rapid and joint-localized increase in microvascular permeability, a process that requires histamine and serotonin (19). There are manifold links between the nervous and vascular systems: For example, VEGF, a major stimulant of angiogenesis, also promotes axon growth (20); the SNS and PNS control cardiovascular parameters such as blood pressure and heart rate; and the neurovascular unit, a term encompassing endothelial cells, neurons, astrocytes, pericytes, and extracellular matrix, is increasingly recognized as central to neurodegenerative diseases (21). Hence, we quantified vascular leakage in denervated and sham-operated limbs of K/BxN-serum recipients.…”

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

“…Therefore, the existence of a T3/TR/ EPAS1 pathway in the developing brain provides a number of interesting working hypotheses linking two pathways with broad influence. In particular, it might participate in the regulation by T3 of glucose consumption (36), antioxydant status of cells (37), angiogenesis (38), and neuronal migration (39).…”