Eph and ephrin signaling in the formation of topographic maps

Abstract

The axonal connections between the retina and its midbrain target, the superior colliculus (SC), is mapped topographically, such that the spatial relationships of cell bodies in the retina are maintained when terminating in the SC. Topographic map development uses a Cartesian mapping system such that each axis of the retina is mapped independently. Along the nasal-temporal mapping axis, EphAs and ephrin-As, are graded molecular cues required for topographic mapping while the dorsal-ventral axis is mapped in part via EphB and ephrin-Bs. Because both Ephs and ephrins are cell surface molecules they can signal in the forward and reverse directions. Eph/ephrin signaling leads to changes in cytoskeletal dynamics that lead to actin depolymerization and endocytosis guiding axons via attraction and repulsion.

Figure 1. Expression patterns of Ephs and ephrins in the retinocollicular system

A) The temporal-nasal (T-N) axis of the retina maps along the anterior-posterior (A-P) axis of the SC/OT. Graded expression of EphA and ephrin-A expression patterns in each structure in the mouse are indicated by blue and red bars, respectively. EphAs are expressed high temporally and anteriorly, while ephrin-As are expressed high nasally and posteriorly in complentary gradients. B) The dorsal-ventral (D-V) axis of the retina maps along the lateral-medial (L-M) axis of the SC/OT. Graded EphB and ephrin-B expression patterns in each structure are indicated by blue and red bars, respectively. In the retina, EphBs are expressed in a V > D gradient, while ephrin-Bs are expressed in a complementary D > V gradient. In the SC, EphBs are expressed uniformly across the L-M axis, and ephrin-B1 expression is high at the midline, but is steeply reduced laterally.

Figure 2. Structure of the retinocollicular map in EphA/ephrin-A knockout and transgenic mice

A–B) In wild type mice, the retina is mapped topographically onto the SC. Temporal RGCs (blue dots) map to anterior SC, while nasal RGCs (red dots) project to posterior SC.. Intrinsic optical imaging reveals topography by measuring the visual responses in the SC to a drifting bar along the N-T axis of the retina. Here depicted as a change in coloration as one moves across the retina and SC (B). C–D) Genetic deletion of ephrin-As or EphAs results in abberant topographic map formation. Anatomical tracing reveals multiple termination zones along the A-P axis of the SC for both temporal and nasal RGCs (C). Functionally, this results in areas of the SC with topographically inappropriate responses, with the general polarity of the map intact (D). E–F) Relative levels of EphA expressed are used to map along the A-P axis. In Islet2-EphA3 knock-in mice, half of retinal ganglion cells express exogenous EphA3, resulting in neighboring cells with drastically different EphA expression levels. This results in a duplicated retinocollicular map as assesed by anatomical tracing (E) and functional imaging studies (F).

Figure 3. Signaling pathways downstream of Eph/ephrin binding and termination of cell-cell contact

A) Ephrin binding to Eph receptors initiates intracellular signaling events in both directions, termed “forward” in the Eph containing cells and “reverse” in the ephrin-bearing cells. Binding to EphA receptors (blue) results in activation of the RhoA GTPase via ephexin, a guanine nucleotide exchange factor (GEF), ultimately resulting in growth cone collapse. In addition, regulation of Tsc2, a GEF, and its downstream target, Rheb, results in decreased translation, contributing to growth cone collapse. Reverse signaling through the GPI-linked ephrin-As (red) is mediated by co-receptors, TrkB and p75^NTR, which results in axonal branching and axon repulsion, respectively. Forward signaling through EphB receptors (cyan) results in growth cone attraction or repulsion, depending on cellular context. Reverse signaling through ephrin-Bs (orange) is important for synapse maturation in the SC/OT. B & C) Ephrin signaling and cell-cell contact is terminated in two possible ways. Endocytosis of EphA receptors occurs in a Vav/Rac dependent manner (B). Termination of EphB/ephrin-B receptors can occur in either cell, each dependent on Rac signaling (B). Cleavage of ephrin-As by ADAM10 protease also results in signal termination and EphA receptor endocytosis (C). ADAM10 can associate with either ephrin-As or EphAs.