Mechanisms of retinotopic map development: Ephs, ephrins, and spontaneous correlated retinal activity

This chapter summarizes mechanisms that control the development of retinotopic maps in the brain, focusing on work from our laboratory using as models the projection of retinal ganglion cells (RGCs) to the chick optic tectum (OT) or rodent superior colliculus (SC). The formation of a retinotopic map involves the establishment of an initial, very coarse map that subsequently undergoes large-scale remodeling to generate a refined map. All arbors are formed by interstitial branches that form in a topographically biased manner along RGC axons that overshoot their correct termination zone (TZ) along the anterior-posterior (A-P) axis of the OT/SC. The interstitial branches exhibit directed growth along the lateral-medial (L-M) axis of the OT/SC to position the branch at the topographically correct location, where it arborizes to form the TZ. EphA receptors and ephrin-A ligands control in part RGC axon mapping along the A-P axis by inhibiting branching and arborization posterior to the correct TZ. Ephrin-B1 acts bifunctionally through EphB forward signaling to direct branches along the L-M axis of the OT/SC to their topographically correct site. Computational modeling indicates that multiple graded activities are required along each axis to generate a retinotopic map, and makes several predictions, including: the progressive addition of ephrin-As within the OT/SC, due to its expression on RGC axon branches and arbors, is required to increase topographic specificity in branching and arborization as well as eliminate the initial axon overshoot, and that interactions amongst RGC axons that resemble correlated neural activity are required to drive retinotopic refinement. Analyses of mutant mice that lack early spontaneous retinal waves that correlate activity amongst neighboring RGCs, confirm this modeling prediction and show that correlated activity during an early brief critical period is required to drive the large-scale remodeling of the initially topographically coarse projection into a refined one. In summary, multiple graded guidance molecules, retinal waves and correlated spontaneous RGC activity cooperate to generate retinotopic maps.