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At least 19 recordsLinked to original sources
PubMed2004

Neurochemical and behavioral deficits consequent to expression of a dominant negative EphA5 receptor.

The Eph family tyrosine kinase receptors and their ligands have been linked to axon guidance and topographic mapping of the developing central nervous system. More specifically, the EphA5 receptor has been shown to play a role in development of hippocamposeptal, retinotectal and thalamocortical projections. Recently, a line of transgenic mice was developed which expresses a truncated EphA5 receptor lacking a functional tyrosine kinase domain. In a previous study, axonal tracing revealed that medial hippocampal axons in this strain projected laterally and ventrally away from their normal target area. In the current study, both transgenic and wild-type controls were evaluated in unconditioned (rotorod and locomotor activity) and conditioned (water maze and active avoidance) behavior tasks which tested hippocampal and striatal functioning. Compared to controls, the transgenic strain did not show differences in rotorod motor activity but did show a transient deficit in spatial navigation ability and a consistent impairment in active avoidance. The dominant-negative mutant receptor also resulted in a decrease in striatal dopamine and serotonin concentrations with no change in hippocampal monoamines. Collectively, these data suggest that animals expressing a truncated EphA5 receptor show deficits related to striatal functioning.

Animals↗
PubMed1999

Functional activation of EphA5 receptor does not promote cell proliferation in the aberrant EphA5 expressing human glioblastoma U-118 MG cell line.

Eph receptors are a subfamily of receptor tyrosine kinases (RTKs), that are activated by ephrin ligands and appear to play important roles in axon guidance and cell migration during development of the nervous system. Over-expression or constitutive activation of Eph receptors has been linked with increased proliferation in various tumours. We have recently described lineage aberrant expression of EphA5 in primary human astrocytomas, glioblastomas and in the human glioblastoma U-118 MG cell line. A role for EphA5 expression in these tumours is not apparent, and we have investigated the cellular effects of EphA5 activation using the human glioblastoma U-118 MG cell line as a model. Immunofluorescent staining demonstrated cell surface expression of EphA5. Activation of the EphA5 receptor using an ephrin-A1 recombinant fusion protein resulted in tyrosine phosphorylation of EphA5 in a time-dependent manner. Exposure of U-118 MG glioblastoma cells to ephrin-A1 did not result in significant spontaneous or FCS-stimulated cell proliferation, though a marginal decrease was observed. This is in converse to the effects of Eph activation in other tumour cell lines, and is the first study to investigate EphA5 in glioblastoma cell lines.

Cell Division↗
PubMed1997

Regulation of topographic projection by the Eph family receptor Bsk (EphA5) and its ligands.

Topographic projection is a general feature of brain architecture and is critical for appropriate information processing and coding. Nevertheless, little is known about the mechanisms that govern topographic organization. The Eph family receptor tyrosine kinases and ligands have recently been implicated in the specification of topographic maps. We have shown that Bsk, an Eph family receptor, and its ligands are expressed in a complementary fashion in neurons and targets, respectively, in several neural systems. For example, in the hippocampus, Bsk is expressed in an increasing lateral to medial gradient. In contrast, at least three different ligands, viz., Elf-1, LERK3/Ehk1-L, and AL-1/RAGS/LERK7, are transcribed in complementary (opposing) gradients in the hippocampal subcortical target, the lateral septum. However, the spatial and temporal distribution of the ligands are different, such that combinatorially they specify the full target region during development. Consistent with a key role in hippocamposeptal topographic projection, the ligands selectively inhibit the growth of the topographically inappropriate medial hippocampal neurites but sustain the growth of the appropriate lateral neurites. Our studies indicate that the interaction of Bsk and its ligands restricts the receptor-positive medial neurons to the topographically appropriate, ligand-poor dorsal septal target. In addition to the hippocamposeptal system, Bsk and its ligands are also expressed in afferents and targets of several other systems, including the olfactory and the retinotectal systems. Consequently, Bsk and its ligands may play important roles in neuron-target interactions in multiple neural circuits.

Animals↗
PubMed2003

EphA/ephrin-A interactions regulate epileptogenesis and activity-dependent axonal sprouting in adult rats.

The Eph family of tyrosine kinase receptors and their ligands, ephrins, are distributed in gradients and serve as molecular guidance cues for axonal patterning during neuronal development. Most of these molecules are also expressed in mature brain. Thus, we examine here the potential roles of such molecules in plasticity and activity-dependent mossy fiber sprouting of adult CNS. We show that the ligand ephrin-A3 and the receptor EphA5 are expressed in complementary gradients in the adult rat mossy fiber system. Using the kindling model, we demonstrate that exogenous immunoadhesins that affect the interaction of endogenous EphA receptors and ephrin-A ligands modulate the development of kindling, one type of long-term plasticity, in mature rat brain. These immunoadhesins, combined with epileptogenic stimulations, alter both the extent and the pattern of collateral axonal sprouting in the mossy fiber pathway. Our results suggest that EphA receptors and ephrin-A ligands modify neuronal plasticity and may serve as spatial cues that modulate the development and pattern of activation-dependent axonal growth in adult CNS.

Animals↗
PubMed2000

Expression of EphA5 during development of the olfactory nerve pathway in rat.

The olfactory neuroepithelium is a highly plastic region of the nervous system that undergoes continual turnover of primary olfactory neurons throughout life. The mechanisms responsible for persistent growth and guidance of primary olfactory axons along the olfactory nerve are unknown. In the present study, we used antibodies against the Eph-related receptor, EphA5, to localise EphA5, and recombinant EphA5-IgG fusion protein to localise its ligands. We found that although both EphA5 and its ligands were both expressed by primary olfactory neurons within the embryonic olfactory nerve pathway, there was no graded or complementary expression pattern. In contrast, the expression patterns altered postnatally such that primary olfactory neurons expressed the ligands, whereas the second-order olfactory neurons, the mitral cells, expressed EphA5. The role of EphA5 was analysed by blocking EphA5-ligand interactions in explant cultures of olfactory neuroepithelium using anti-EphA5 antibodies and recombinant EphA5. These perturbations reduced neurite outgrowth from explant cultures and suggest that intrafascicular axon repulsion may serve to limit adhesion and optimise conditions for axon growth.

Aging↗
PubMed1998

Topographic guidance labels in a sensory projection to the forebrain.

Visual connections to the mammalian forebrain are known to be patterned by neural activity, but it remains unknown whether the map topography of such higher sensory projections depends on axon guidance labels. Here, we show complementary expression and binding for the receptor EphA5 in mouse retina and its ligands ephrin-A2 and ephrin-A5 in multiple retinal targets, including the major forebrain target, the dorsal lateral geniculate nucleus (dLGN). These ligands can act in vitro as topographically specific repellents for mammalian retinal axons and are necessary for normal dLGN mapping in vivo. The results suggest a general and economic modular mechanism for brain mapping whereby a projecting field is mapped onto multiple targets by repeated use of the same labels. They also indicate the nature of a coordinate system for the mapping of sensory connections to the forebrain.

Aging↗
PubMed1998

Regulation of thalamic neurite outgrowth by the Eph ligand ephrin-A5: implications in the development of thalamocortical projections.

The cerebral cortex is parcellated into different functional domains that receive distinct inputs from other cortical and subcortical regions. The molecular mechanisms underlying the specificity of connections of cortical afferents remain unclear. We report here that the Eph family tyrosine kinase receptor EphA5 and the ligand ephrin-A5 may play a key role in the exclusion of the limbic thalamic afferents from the sensorimotor cortex by mediating repulsive interactions. In situ hybridization shows that the EphA5 transcript is expressed at high levels in both cortical and subcortical limbic regions, including the frontal cortex, the subiculum, and the medial thalamic nuclei. In contrast, ephrin-A5 is transcribed abundantly in the sensorimotor cortex. Consistent with the complementary expression, the ligand inhibited dramatically the growth of neurites from neurons isolated from the medial thalamus but was permissive for the growth of neurites from lateral thalamic neurons, which is primarily nonlimbic. Similarly, the growth of neurites from Eph-A5-expressing neurons isolated from the subiculum was inhibited by ephrin-A5. Our studies suggest that the Eph family ligand ephrin-A5 serves as a general inhibitor of axonal growth from limbic neurons, which may serve to prevent innervation of inappropriate primary sensorimotor regions, thus contributing to the generation of specificity of thalamic cortical afferents.

Animals↗
PubMed1999

Regulation of learning by EphA receptors: a protein targeting study.

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.

Animals↗
PubMed2005

Eph/ephrin expression in the adult rat visual system following localized retinal lesions: localized and transneuronal up-regulation in the retina and superior colliculus.

Following unilateral optic nerve section in adult PVG hooded rat, the axon guidance cue ephrin-A2 is up-regulated in caudal but not rostral superior colliculus (SC) and the EphA5 receptor is down-regulated in axotomised retinal ganglion cells (RGCs). Changes occur bilaterally despite the retino-collicular projection being mostly crossed. Here we investigate the dynamics of Eph/ephrin expression using in situ hybridization and semi-quantitative immunohistochemistry after localized retinal lesions. Unilateral krypton laser lesions to dorso-nasal retina ablated contralaterally projecting RGCs (DN group); ventro-temporal lesions ablated contralaterally and ipsilaterally projecting RGCs (VT group). Lesions of the entire retina served as controls (Total group). Results are compared to normal animals in which tectal ephrin-A2 and retinal EphA5 are expressed, respectively, as shallow ascending rostro-caudal and naso-temporal gradients. In both SCs of DN and Total groups, tectal ephrin-A2 was up-regulated caudally; in the VT group, expression remained normal bilaterally. Unilateral collicular ablation indicated that bilateral changes in ephrin-A2 expression are mediated via intercollicular pathways. EphA5 expression in the VT group was elevated in the intact nasal region of experimental retinae. For each experimental group, EphA5 expression was also elevated in nasal retina of the opposite eye, resulting in uniform expression across the naso-temporal axis. Up-regulation of ephrin-A2 in caudal, but not rostral, SC suggests the enhancement of developmental positional information as a result of injury. Bilateral increases in retinal EphA5 expression demonstrate that signals for up-regulation operate interocularly. The study demonstrates that signals regulating guidance cue expression are both localized and relayed transneuronally.

Animals↗
PubMed1999

Marsupial retinocollicular system shows differential expression of messenger RNA encoding EphA receptors and their ligands during development.

The protracted development of the wallaby (Macropus eugenii) has allowed study of messenger RNAs encoding Eph receptors EphA3 and EphA7 and ligands ephrin-A2 and -A5 in the retina and superior colliculus at intervals throughout the development of the retinocollicular projection: from birth, before retinal innervation, to postnatal day 95, when the projection is mature. Reverse transcription-polymerase chain reaction showed messenger RNAs for both receptors and ligands were expressed at all ages. EphA7 was expressed more highly in the rostral superior colliculus. Ephrin-A2 and -A5 were expressed more highly in the caudal colliculus. EphA3 was expressed in a complementary manner, more highly in temporal than in nasal retina. There are higher levels of expression of the ligands when the projection is only coarsely topographically organised. This suggests a role for them and their receptor EphA3 in this stage, by repulsive interactions which restrict temporal axons to rostral superior colliculus. This is the first account in a marsupial mammal of the appearance of this molecular family, substantiating its ubiquitous role in topographically organised neuronal connections. Nevertheless, expression is not the same as in the mouse, suggesting differences in the details of topographic coding between species.

Animals↗
PubMed2005

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

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.

Animals↗
PubMed1994

Isolation and characterization of Bsk, a growth factor receptor-like tyrosine kinase associated with the limbic system.

Neuronal degeneration has been shown to be involved in various neurological disorders. Growth/trophic factors and their receptors are known to be important for the regeneration and survival of neurons. We report here the molecular cloning of a receptor-like protein tyrosine kinase, bsk, (for brain specific kinase). Bsk is highly related to the eph/elk receptor-like kinase family members. Northern blot analysis shows that it is expressed specifically in the brain, with no expression detected in adult heart, spleen, lung, liver, skeletal muscle, and kidney. In situ hybridization analysis of adult mouse brain sections indicates that bsk is expressed at high levels in the hippocampus, tenia tecta, indusium griseum, and the piriform cortex, major components of the limbic system that are important for learning and memory. In addition, elevated levels of expression are found in other areas of the limbic system such as the amygdala, medial septum, and nucleus of the diagonal band, and in the olfactory bulb, which has close connections to the limbic system. The highest level of expression is found in the CA3 region of the hippocampus and the pyramidal cell layer of the piriform cortex. In 16.5 day mouse embryos, bsk is expressed predominantly in the primordial cortex of the telencephalon. An antibody against a C-terminal peptide of bsk recognized a 105 kD protein in the 16.5 day embryonic head extract. Our analysis shows that bsk is a growth factor receptor-like protein tyrosine kinase and that its greatest expression in the adult brain is associated with components of the limbic system.

Amino Acid Sequence↗
PubMed2006

Follow your nose: axon pathfinding in olfactory map formation.

Two new studies report how discrete identities of olfactory sensory neurons are converted into a spatial map of axonal connections (Imai et al., 2006; Serizawa et al., 2006). They find that levels of cAMP signals derived from olfactory receptors (ORs) can direct targeting of axons along an axis, and that ORs and neural activity regulate expression of adhesion/guidance molecules in mosaic patterns that can sort axons into discrete locations.

Animals↗
PubMed2005

Dissociation of corticothalamic and thalamocortical axon targeting by an EphA7-mediated mechanism.

Molecular mechanisms generating the topographic organization of corticothalamic (CT) circuits, which comprise more than three-quarters of the synaptic inputs onto sensory relay neurons, and their interdependence with thalamocortical (TC) axon development are unknown. Using in utero electroporation-mediated gene transfer, we show that EphA7-mediated signaling on neocortical axons controls the within-nucleus topography of CT projections in the thalamus. Notably, CT axons that mis-express EphA7 do not shift the relative positioning of their pathway within the subcortical telencephalon (ST), indicating that they do not depend upon EphA7/ephrin-A signaling in the ST for establishing this topography. Moreover, mis-expression of cortical EphA7 results in disrupted topography of CT projections, but unchanged inter- and intra-areal topography of TC projections. Our results support a model in which EphA/ephrin-A signaling controls independently the precision with which CT and TC projections develop, yet is essential for establishing their topographic reciprocity.

Animals↗
PubMed2001

Semiquantitative expression analysis of ephrine-receptor tyrosine kinase mRNA's in a rat model of traumatic brain injury.

The molecular mechanisms involved in recovery of function of the central nervous system (CNS) after injury to the brain are incompletely understood. Here the expression of ephrine (Eph) kinases following traumatic brain injury (subdural haematoma) was analysed in order to find out whether these developmentally regulated genes may be involved in tissue remodelling after brain damage. mRNA was isolated from ipsilateral cortices 7, 18, and 28 days after surgery and semiquantitative reverse transcription-polymerase chain reaction was performed. Most Eph kinases did not show significant regulation at gene expression level during the time course of recovery from acute brain injury but there is some evidence that mRNA of EphB1 might be slightly upregulated.

Animals↗
PubMed2002

Can Eph receptors stimulate the mind?

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.

Animals↗
PubMed2002

Expression of EphA receptors and ligands during chick cerebellar development.

The cerebellum is a modular structure that integrates information in a topographical manner. The membrane receptors of the Eph family and their ligands play important roles in early regionalization, as well as in the formation of topographic connections of the nervous system. Here, we show that the expression of the Eph receptors -A4 and -A7, and of their ligands ephrin-A5 and -A2 correlates with the establishment of territories along the rostro-caudal axis and with the formation of topographically organized connections between the cortex and the cerebellar nuclei. While some sites where co-expression of receptors and ligands are evident, their relative expression mainly define sharp limits along the rostro-caudal axis and, at later stages, complementary gradients in the Purkinje cell layer and the deep cerebellar nuclei.

Animals↗