VEGF Signaling through Neuropilin 1 Guides Commissural Axon Crossing at the Optic Chiasm

Abstract

SummaryDuring development, the axons of retinal ganglion cell (RGC) neurons must decide whether to cross or avoid the midline at the optic chiasm to project to targets on both sides of the brain. By combining genetic analyses with in vitro assays, we show that neuropilin 1 (NRP1) promotes contralateral RGC projection in mammals. Unexpectedly, the NRP1 ligand involved is not an axon guidance cue of the class 3 semaphorin family, but VEGF164, the neuropilin-binding isoform of the classical vascular growth factor VEGF-A. VEGF164 is expressed at the chiasm midline and is required for normal contralateral growth in vivo. In outgrowth and growth cone turning assays, VEGF164 acts directly on NRP1-expressing contralateral RGCs to provide growth-promoting and chemoattractive signals. These findings have identified a permissive midline signal for axons at the chiasm midline and provide in vivo evidence that VEGF-A is an essential axon guidance cue.

Diverse roles for VEGF-A in the nervous system

“…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.…”

Motoneuronal Sema3C is essential for setting stereotyped motor tract positioning in limb-derived chemotropic semaphorins

“…Our finding that Sema3C intrinsic effects rely on the regulation of Nrp1 and Nrp2 raises an even broader potential for Sema3C to regulate the responsiveness to other Nrp ligands, such as VEGF (Neufeld et al, 2002;Erskine et al, 2011). Until now, the mechanisms underlying the integration of multiple extracellular guidance signals are poorly known and Sema3C thus appears as an interesting example of how a neuron-derived factor can participate in the program integrating guidance information by the growth cone.…”

Collapsin Response Mediator Proteins (CRMPs) Are a New Class of Microtubule-associated Protein (MAP) That Selectively Interacts with Assembled Microtubules via a Taxol-sensitive Binding Interaction

“…Class 3 semaphorins, which include Sema3A, are structurally conserved secreted proteins. Neuropilin-1/PlexinA holoreceptor transmits signals from Sema3A to affect multiple processes including axon and dendrite specification (7,8). This involves the activation of various kinases including Rho-kinase (ROCK) and CDK5.…”