Ephrin-A binding and EphA receptor expression delineate the matrix compartment of the striatum.
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The striatum integrates limbic and neocortical inputs to regulate sensorimotor and psychomotor behaviors. This function is dependent on the segregation of striatal projection neurons into anatomical and functional components, such as the striosome and matrix compartments. In the present study the association of ephrin-A cell surface ligands and EphA receptor tyrosine kinases (RTKs) with the organization of these compartments was determined in postnatal rats. Ephrin-A1 and ephrin-A4 selectively bind to EphA receptors on neurons restricted to the matrix compartment. Binding is absent from the striosomes, which were identified by mu-opioid receptor immunostaining. In contrast, ephrin-A2, ephrin-A3, and ephrin-A5 exhibit a different mosaic binding pattern that appears to define a subset of matrix neurons. In situ hybridization for EphA RTKs reveals that the two different ligand binding patterns strictly match the mRNA expression patterns of EphA4 and EphA7. Ligand-receptor binding assays indicate that ephrin-A1 and ephrin-A4 selectively bind EphA4 but not EphA7 in the lysates of striatal tissue. Conversely, ephrin-A2, ephrin-A3, and ephrin-A5 bind EphA7 but not EphA4. These observations implicate selective interactions between ephrin-A molecules and EphA RTKs as potential mechanisms for regulating the compartmental organization of the striatum. (+info)
Regulation of learning by EphA receptors: a protein targeting study.
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EphA family receptor tyrosine kinases and their ephrin-A ligands are involved in patterning axonal connections during brain development, but until now a role for these molecules in the mature brain had not been elucidated. Here, we show that both the EphA5 receptor and its ephrin-A ligands (2 and 5) are expressed in the adult mouse hippocampus, and the EphA5 protein is present in a phosphorylated form. Because there are no pharmacological agents available for EphA receptors, we designed recombinant immunoadhesins that specifically bind to the receptor binding site of the ephrin-A ligand (antagonist) or the ligand binding site of the EphA receptor (agonist) and thus target EphA function. We demonstrate that intrahippocampal infusion of an EphA antagonist immunoadhesin leads to impaired performance in two behavioral paradigms, T-maze spontaneous alternation and context-dependent fear conditioning, sensitive to hippocampal function, whereas activation of EphA by infusion of an agonist immunoadhesin results in enhanced performance on these tasks. Because the two behavioral tasks have different motivational, perceptual, and motor requirements, we infer the changes were not caused by these performance factors but rather to cognitive alterations. We also find bidirectional changes in gene expression and in electrophysiological measures of synaptic efficacy that correlate with the behavioral results. Thus, EphA receptors and their ligands are implicated as mediators of plasticity in the adult mammalian brain. (+info)
Selective inhibition of spinal cord neurite outgrowth and cell survival by the Eph family ligand ephrin-A5.
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The Eph family tyrosine kinase receptors and their ligands, the ephrins, have been shown to play critical roles in cell migration, tissue morphogenesis, and axonal guidance in many different systems. However, their function in the spinal cord has not been examined carefully. We showed in this study that several Eph receptors, including EphA3, Eph A4, and Eph A5, are expressed in the ventral spinal cord in partially overlapping patterns, with EphA5 exhibiting the most widespread transcription in the entire ventral spinal cord during early development. Complementary to the receptor expression, a ligand of these receptors, ephrin-A5, is transcribed in the dorsal half of the spinal cord. Consistent with the spatial location of receptor expression, the ligand selectively inhibits neurite outgrowth and induces cell death of the ventral, but not the dorsal, spinal cord neurons. These observations suggest that interactions between the Eph family receptors and ligands exerts negative influences on ventral spinal cord neurons and thus may play important roles in regulating morphogenesis and axon guidance in the spinal cord. (+info)
Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling.
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Topographic maps are a fundamental feature of sensory representations in nervous systems. The formation of one such map, defined by the connection of ganglion cells in the retina to their targets in the superior colliculus of the midbrain, is thought to depend upon an interaction between complementary gradients of retinal EphA receptors and collicular ephrin-A ligands. We have tested this hypothesis by using gene targeting to elevate EphA receptor expression in a subset of mouse ganglion cells, thereby producing two intermingled ganglion cell populations that express distinct EphA receptor gradients. We find that these two populations form separate maps in the colliculus, which can be predicted as a function of the net EphA receptor level that a given ganglion cell expresses relative to its neighbors. (+info)
Two homeobox genes define the domain of EphA3 expression in the developing chick retina.
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Graded expression of the Eph receptor EphA3 in the retina and its two ligands, ephrin A2 and ephrin A5 in the optic tectum, the primary target of retinal axons, have been implicated in the formation of the retinotectal projection map. Two homeobox containing genes, SOHo1 and GH6, are expressed in a nasal-high, temporal-low pattern during early retinal development, and thus in opposing gradients to EphA3. Retroviral misexpression of SOHo1 or GH6 completely and specifically repressed EphA3 expression in the neural retina, but not in other parts of the central nervous system, such as the optic tectum. Under these conditions, some temporal ganglion cell axons overshot their expected termination zones in the rostral optic tectum, terminating aberrantly at more posterior locations. However, the majority of ganglion cell axons mapped to the appropriate rostrocaudal locations, although they formed somewhat more diffuse termination zones. These findings indicate that other mechanisms, in addition to differential EphA3 expression in the neural retina, are required for retinal ganglion axons to map to the appropriate rostrocaudal locations in the optic tectum. They further suggest that the control of topographic specificity along the retinal nasal-temporal axis is split into several independent pathways already at a very early time in development. (+info)
A role for the EphA family in the topographic targeting of vomeronasal axons.
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We have investigated the role of the Eph family of receptor tyrosine kinases and their ligands in the establishment of the vomeronasal projection in the mouse. Our data show intriguing differential expression patterns of ephrin-A5 on vomeronasal axons and of EphA6 in the accessory olfactory bulb (AOB), such that axons with high ligand concentration project onto regions of the AOB with high receptor concentration and vice versa. These data suggest a mechanism for development of this projection that is the opposite of the repellent interaction between Eph receptors and ligands observed in other systems. In support of this idea, when given the choice of whether to grow on lanes containing EphA-F(c)/laminin or F(c)/laminin protein (in the stripe assay), vomeronasal axons prefer to grow on EphA-F(c)/laminin. Analysis of ephrin-A5 mutant mice revealed a disturbance of the topographic targeting of vomeronasal axons to the AOB. In summary, these data, which are derived from in vitro and in vivo experiments, indicate an important role of the EphA family in setting up the vomeronasal projection. (+info)
Can Eph receptors stimulate the mind?
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The Eph receptors are multitalented tyrosine kinases capable of performing many tasks. The receptors together with their ligands--the ephrins--are well known to play a critical role in the initial assembly of neuronal circuits in the embryo. However, the recently discovered function of these receptors in the adult brain is now receiving significant acclaim. Three new articles show that the Eph receptors continue to be important in modifying the strength of existing neuronal connections (synapses). They do so in close association with at least one family of ion channels, the NMDA receptors. (+info)
Mistargeting hippocampal axons by expression of a truncated Eph receptor.
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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. (+info)