Retinotopic order in the absence of axon competition

Abstract

The retinotectal projection has long been studied experimentally and theoretically, as a model for the formation of topographic brain maps. Neighbouring retinal ganglion cells (RGCs) project their axons to neighbouring positions in the optic tectum, thus re-establishing a continuous neural representation of visual space. Mapping along this axis requires chemorepellent signalling from tectal cells, expressing ephrin-A ligands, to retinal growth cones, expressing EphA receptors. High concentrations of ephrin A, increasing from anterior to posterior, prevent temporal axons from invading the posterior tectum. However, the force that drives nasal axons to extend past the anterior tectum and terminate in posterior regions remains to be identified. We tested whether axon-axon interactions, such as competition, are required for posterior tectum innervation. By transplanting blastomeres from a wild-type (WT) zebrafish into a lakritz (lak) mutant, which lacks all RGCs, we created chimaeras with eyes that contained single RGCs. These solitary RGCs often extended axons into the tectum, where they branched to form a terminal arbor. Here we show that the distal tips of these arbors were positioned at retinotopically appropriate positions, ruling out an essential role for competition in innervation of the ephrin-A-rich posterior tectum. However, solitary arbors were larger and more complex than under normal, crowded conditions, owing to a lack of pruning of proximal branches during refinement of the retinotectal projection. We conclude that dense innervation is not required for targeting of retinal axons within the zebrafish tectum but serves to restrict arbor size and shape.

Functional Topography and Integration of the Contralateral and Ipsilateral Retinocollicular Projections ofEphrin-A−/−Mice

“…The process requires spatially and chronologically correlated electrical activity and is thus optimal in a densely packed cell population such as contralaterally projecting RGCs. In contrast, greater distances between RCG somata, e.g., between ipsilaterally projecting RGCs, reduce temporospatial electrical synchrony and, thus, the impact of activity-dependent processes so that, at the extreme, a single-neuron projection with no activity-dependent competition has enlarged unpruned axon terminal fields (Gosse et al, 2008). Therefore, the lack of ephrin-As in our mice is likely to have a more severe impact on the ipsilateral compared with the contralateral projection because of weaker activity-dependent refinement.…”

Conformal geometry of the retinal nerve fiber layer

“…Let us assume, for the moment, that all such morphogens act independently (for example, by modulating the activity of some common receptor) without interaction terms and without competition between different axons. One of the reviewers kindly called our attention to an example of such behavior for the retinotectal map (6). Then, the overall effect can be encapsulated in one potential function defined throughout the retina, with the axon growing in the direction of the potential's steepest gradient.…”

In vivo imaging of the zebrafish retinotectal map

“…Competition between axons does not contribute to an axonal arbors initial position in the retinotectal map in zebrafish [108]. than axon-axon interactions [183], are necessary for the initial topographic arrangement.…”

“…In zebrafish, which develop rapidly, the initial map is rough but present. A single zebrafish RGC in an empty tectum, without any competitors at all, can grow to roughly the correct topographic location, even if it does remain larger, especially with extra branches on its rostral extent [108].…”

“…In some cases, the empty edges of the SC are innervated incorrectly by the ipsilateral axons, rather than the correct contralateral ones [198]. However, competition does not seem to be a strong a force in the initial topographic Ephrin-A2 and ephrin-A5b knockdown map formation in zebrafish [108].…”