Ephrin‐A2 and ‐A5 influence patterning of normal and novel retinal projections to the thalamus: Conserved mapping mechanisms in visual and auditory thalamic targets

Abstract

Sensory axons are targeted to modality-specific nuclei in the thalamus. Retinal ganglion cell axons project retinotopically to their principal thalamic target, the dorsal lateral geniculate nucleus (LGd), in a pattern likely dictated by the expression of molecular gradients in the LGd. Deafferenting the auditory thalamus induces retinal axons to innervate the medial geniculate nucleus (MGN). These retino-MGN projections also show retinotopic organization. Here we show that ephrin-A2 and -A5, which are expressed in similar gradients in the MGN and LGd, can be used to pattern novel retinal projections in the MGN. As in the LGd, retinal axons from each eye terminate in discrete eye-specific zones in the MGN of rewired wild-type and ephrin-A2/A5 knockout mice. However, ipsilateral eye axons, which arise from retinal regions of high EphA5 receptor expression and represent central visual field, terminate in markedly different ways in the two mice. In rewired wild-type mice, ipsilateral axons specifically avoid areas of high ephrin expression in the MGN. In rewired ephrin knockout mice, ipsilateral projections shift in location and spread more broadly, leading to an expanded representation of the ipsilateral eye in the MGN. Similarly, ipsilateral projections to the LGd in ephrin knockout mice are shifted and are more widespread than in the LGd of wild-type mice. In the MGN, as in the LGd, terminations from the two eyes show little overlap even in the knockout mice, suggesting that local interocular segregation occurs regardless of other patterning determinants. Our data demonstrate that graded topographic labels, such as the ephrins, can serve to shape multiple related aspects of afferent patterning, including topographic mapping and the extent and spread of eye-specific projections. Furthermore, when mapping labels and other cues are expressed in multiple target zones, novel projections are patterned according to rules that operate in their canonical targets.

Mechanisms Underlying Development of Visual Maps and Receptive Fields

“…Thus, timed ephrin-A expression in theLGNregulates the early critical period for eye-specificLGNlayer formation observed in other studies (Muir-Robinson et al 2002, Huberman et al 2002. Also, in experiments where RGC axons are experimentally rewired to novel, non-visual targets, ipsilateral RGC axons avoid regions of high ephrin-A expression and segregate from contralateral eye RGC axons in those novel targets (Ellsworth et al 2005), consistent with the idea that the expression pattern of ephrin-As unique to each subcortical RGC target dictates the characteristic spatial organization of eye-specific territories that will form in that target.…”

EphA4 misexpression alters tonotopic projections in the auditory brainstem

“…Eph proteins are expressed in several areas of the auditory pathway. In the VIIIth nerve, auditory axons express EphA4 in a low-to-high frequency gradient (Siddiqui and Cramer, 2005), and ephrin-A ligands show graded expression in the medial geniculate nucleus of the thalamus (Lyckman et al, 2001;Ellsworth et al, 2005). Functional studies are needed to elucidate the roles of these proteins throughout the auditory pathway.…”

Remodeling of Synaptic Structure in Sensory Cortical AreasIn Vivo

“…Third, rewiring may affect too few synapses to be detected with our imaging paradigm. This is unlikely because retinal projections to the auditory thalamus are extensive, spanning the entire ventral division of the MGN (Ellsworth et al, 2005). Furthermore, rewiring elicits functional changes in the network architecture of auditory cortex and can drive visual responses and behavior (Sharma et al, 2000;von Melchner et al, 2000;Newton et al, 2004).…”