Mistargeting hippocampal axons by expression of a truncated Eph receptor

Abstract

Topographic mapping of axon terminals is a general principle of neural architecture that underlies the interconnections among many neural structures. The Eph family tyrosine kinase receptors and their ligands, the ephrins, have been implicated in the formation of topographic projection maps. We show that multiple Eph receptors and ligands are expressed in the hippocampus and its major subcortical projection target, the lateral septum, and that expression of a truncated Eph receptor in the mouse brain results in a pronounced alteration of the hippocamposeptal topographic map. Our observations provide strong support for a critical role of Eph family guidance factors in regulating ontogeny of hippocampal projections.I nformation encoding as topographic maps, which reflects the spatial organization of sensory surfaces and body effectors, is a fundamental mechanism of nervous system function (1, 2). Such topographic representation is critically dependent on precise ordering of axon projections, which maintains the spatial organization of neurons in synaptic connections with target neurons. It has been suggested that topographic axon connections allow transfer of spatial information in the sensory systems (3). In the eye, retinal axons form an inverted projection map in the tectum, with dorsal axons projecting to the ventral tectum, and ventral axons to the dorsal tectum. Similarly, retinal ganglion neurons in the temporal and nasal sides send axons to the anterior and posterior regions of the tectum, respectively (4). Comparable mechanisms may also operate in the limbic circuits, where learning, memory, and emotional responses are elaborated. For example, the hippocampus sends axons topographically to the lateral septum, with dorsomedial neurons projecting to the dorsomedial area of the target, and ventrolateral neurons projecting to the ventrolateral septal region (5, 6). Similarity in organizational principles between limbic circuits and sensory systems suggests that learning, memory, and emotions may be governed by the same spatial constraints as sensory information processing.Based on analyses of regenerating retinal axons, Roger Sperry (7) proposed that axons and target neurons carry specific cytochemical identification tags, and that each axon makes synaptic connections only with neurons carrying matching affinity tags. These tags may be distributed as gradients in the projecting and target fields to specify topographic maps. Recent expression and functional studies suggest that ephrins and their receptors serve as the postulated chemoaffinity guidance tags. The ephrins are a family of cell surface molecules that are ligands of the Eph family tyrosine kinase receptors (8). The Eph receptors, EphA3 in the chicken and EphA5͞A6 in the mouse retina, are expressed in a nasal (low) to temporal (high) gradient (3, 9, 10). Complementary to the receptor gradient, the ligands ephrin-A2 and -A5 constitute an anterior (low) to posterior (high) gradient in the optic tectum (9, 11-13). Disruption of the ligand gradient by re...

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

“…Among them are Epha6, a tyrosine kinase receptor important for axon guidance, as well as Slc5a7, which encodes choline transporter responsible for proper choline uptake along the synapse. 18,19 Eleven genes are associated with cellular development/ death ( Figure 1c). Among them, downregulation of Mc1r and downregulation of Glra1 are two examples that show functional relevance to AS.…”

Plasticity of Neuron-Glial Interactions Mediated by Astrocytic EphARs

“…EphARs are also critical in establishing topographically organized hippocampal-septal projections (Yue et al, 2002). There is considerable evidence that activation of EphB receptors regulates the structure and function of excitatory synapses in the hippocampus (Dalva et al, 2000;Grunwald et al, 2001;Penzes et al, 2003).…”

Changes in attack behavior and activity in EphA5 knockout mice

“…The function of the EphA5 receptor is best characterized as an axon guidance molecule during neural development (Cheng et al, 1995;Yue et al, 2002). The EphA5 receptor and its ligand act as a repellant cue that prevents axons from entering inappropriate territories, thus restricting the cells to specific pathways during the migratory process (Wilkinson, 2001).…”

“…It has been demonstrated that this interaction causes inhibition of the neurite outgrowth of hippocampal, striatal, retinal, and cortical neurons, while it enhances the neurite outgrowth of sympathetic neurons and stimulates neurite sprouting of cortical neurons in vitro (Brownlee et al, 2000;Gao et al, 2000Gao et al, , 1998aGao et al, , 1996. At the circuit level, overexpression of a truncated form of EphA5 receptor resulted in a miswiring of the hippocamposeptal pathway and corpus callosum connections in vivo (Yue et al, 2002). In particular, medial hippocampal neurons with high expression level of the EphA5 receptor projected to both the ventral and lateral part of the target site while lateral hippocampal neurons with relatively low EphA5 receptor expression did not exhibit any obvious alteration in their projection pattern.…”

“…Their interaction triggers growth cone collapse and inhibits the neurite outgrowth in vitro. Furthermore, abnormal expression of these molecules results in the disruption of axonal pathfinding and mid-line crossing in vivo Hu et al, 2003;Yue et al, 2002).…”