Abstract
BackgroundRetinotopic projection onto the tectum/colliculus constitutes the most studied model of topographic mapping and Eph receptors and their ligands, the ephrins, are the best characterized molecular system involved in this process. Ephrin-As, expressed in an increasing rostro-caudal gradient in the tectum/colliculus, repel temporal retinal ganglion cell (RGC) axons from the caudal tectum and inhibit their branching posterior to their termination zones. However, there are conflicting data regarding the nature of the second force that guides nasal axons to invade and branch only in the caudal tectum/colliculus. The predominant model postulates that this second force is produced by a decreasing rostro-caudal gradient of EphA7 which repels nasal optic fibers and prevents their branching in the rostral tectum/colliculus. However, as optic fibers invade the tectum/colliculus growing throughout this gradient, this model cannot explain how the axons grow throughout this repellent molecule.Methodology/Principal FindingsBy using chicken retinal cultures we showed that EphA3 ectodomain stimulates nasal RGC axon growth in a concentration dependent way. Moreover, we showed that nasal axons choose growing on EphA3-expressing cells and that EphA3 diminishes the density of interstitial filopodia in nasal RGC axons. Accordingly, in vivo EphA3 ectodomain misexpression directs nasal optic fibers toward the caudal tectum preventing their branching in the rostral tectum.ConclusionsWe demonstrated in vitro and in vivo that EphA3 ectodomain (which is expressed in a decreasing rostro-caudal gradient in the tectum) is necessary for topographic mapping by stimulating the nasal axon growth toward the caudal tectum and inhibiting their branching in the rostral tectum. Furthermore, the ability of EphA3 of stimulating axon growth allows understanding how optic fibers invade the tectum growing throughout this molecular gradient. Therefore, opposing tectal gradients of repellent ephrin-As and of axon growth stimulating EphA3 complement each other to map optic fibers along the rostro-caudal tectal axis.
Highlights
Nervous system functions depend upon precisely organized neuronal connections
We demonstrated in vitro and in vivo that EphA3 ectodomain is necessary for topographic mapping by stimulating the nasal axon growth toward the caudal tectum and inhibiting their branching in the rostral tectum
Through functional in vitro and in vivo experiments, we demonstrated that the tectal gradient of EphA3 ectodomain is necessary to map nasal retinal ganglion cell (RGC) axons on tectal surface by promoting nasal RGC axon growth toward the caudal tectum and inhibiting branching rostrally to their appropriate termination zone
Summary
Nervous system functions depend upon precisely organized neuronal connections. Many axons establish an ordered arrangement in their target in such way that neighbouring cells project to neighbouring parts in the target forming a topographic map [1]. The main model to study the development of topographic maps is the retinal ganglion cell (RGC) projection to the optic tectum or superior colliculus, which is organized in two orthogonally oriented axes. RGC axons invade the chicken tectum from the rostral pole and follow its developmental gradient axis toward the caudal pole [1,3,4,5]. Ephrin-As, expressed in an increasing rostro-caudal gradient in the tectum/colliculus, repel temporal retinal ganglion cell (RGC) axons from the caudal tectum and inhibit their branching posterior to their termination zones. The predominant model postulates that this second force is produced by a decreasing rostrocaudal gradient of EphA7 which repels nasal optic fibers and prevents their branching in the rostral tectum/colliculus. As optic fibers invade the tectum/colliculus growing throughout this gradient, this model cannot explain how the axons grow throughout this repellent molecule
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