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PubMed1999

Induction of Eph B3 after spinal cord injury.

Spinal cord injury (SCI) in adult rats initiates a cascade of events producing a nonpermissive environment for axonal regeneration. This nonfavorable environment could be due to the expression of repulsive factors. The Eph receptor protein tyrosine kinases and their respective ligands (ephrins) are families of molecules that play a major role in axonal pathfinding and target recognition during central nervous system (CNS) development. Their mechanism of action is mediated by repellent forces between receptor and ligand. The possible role that these molecules play after CNS trauma is unknown. We hypothesized that an increase in the expression of Eph proteins and/or ephrins may be one of the molecular cues that restrict axonal regeneration after SCI. Rats received a contusive SCI at T10 and in situ hybridization studies 7 days posttrauma demonstrated: (i) a marked up-regulation of Eph B3 mRNA in cells located in the white matter at the lesion epicenter, but not rostral or caudal to the injury site, and (ii) an increase in Eph B3 mRNA in neurons in the ventral horn and intermediate zone of the gray matter, rostral and caudal to the lesion. Immunohistochemical analyses localizing Eph B3 protein were consistent with the mRNA results. Colocalization studies performed in injured animals demonstrated increased Eph B3 expression in white matter astrocytes and motor neurons of the gray matter. These results suggest that Eph B3 may contribute to the unfavorable environment for axonal regeneration after SCI.

Animals↗
PubMed1997

cDNA cloning, chromosomal localization, and expression pattern of EPLG8, a new member of the EPLG gene family encoding ligands of EPH-related protein-tyrosine kinase receptors.

By screening a human fetal brain cDNA library under low stringency using cDNA encoding the mouse ligand of Cek5 as a probe, we have isolated a novel cDNA belonging to the EPLG gene family. This family encodes ligands of EPH-related tyrosine kinase receptors. Since the novel gene is the eighth member of the EPLG gene family, it is designated EPLG8. The deduced amino acid sequence of EPLG8 suggests that it encodes a transmembrane protein that is most related to those encoded by EPLG2 and EPLG5. We mapped the EPLG8 gene to human chromosome 17p11.2-p13.1 by PCR screening of human-rodent somatic cell hybrid panels. In the midterm fetus, EPLG8 mRNA is expressed at the highest level in brain, followed by heart, kidney, and lung. In the adult, EPLG8 mRNA expression is restricted to brain. These data suggest that LERK-8, the protein encoded by EPLG8, is important in brain development as well as in its maintenance. Moreover, since levels of EPLG8 expression were particularly high in several forebrain subregions compared to other brain subregions, LERK-8 may play a pivotal role in forebrain function.

Adult↗
PubMed2004

Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2.

Rhomboid-1 is a serine protease that cleaves the membrane domain of the Drosophila EGF-family protein, Spitz, to release a soluble growth factor. Several vertebrate rhomboid-like proteins have been identified, although their substrates and functions remain unknown. The human rhomboid, RHBDL2, cleaves the membrane domain of Drosophila Spitz when the proteins are co-expressed in mammalian cells. However, the membrane domains of several mammalian EGF-family proteins were not cleaved by RHBDL2, suggesting that the endogenous targets of the human protease are not EGF-related factors. We demonstrate that the amino acid sequence at the luminal face of the membrane domain of a substrate protein determines whether it is cleaved by RHBDL2. Based on this finding, we predicted B-type ephrins as potential RHBDL2 substrates. We found that one of these, ephrinB3, was cleaved so efficiently by the protease that little ephrinB3 was detected on the surface of cells co-expressing RHBDL2. These results raise the possibility that RHBDL2-mediated proteolytic processing may regulate intercellular interactions between ephrinB3 and eph receptors.

Amino Acid Sequence↗
PubMed2003

Physiological, anatomical and genetic identification of CPG neurons in the developing mammalian spinal cord.

The basic motor patterns underlying rhythmic limb movements during locomotion are generated by neuronal networks located within the spinal cord. These networks are called Central Pattern Generators (CPGs). Isolated spinal cord preparations from newborn rats and mice have become increasingly important for understanding the organization of the CPG in the mammalian spinal cord. Early studies using these preparations have focused on the overall network structure and the localization of the CPG. In this review we concentrate on recent experiments aimed at identifying and characterizing CPG-interneurons in the rodent. These experiments include the organization and function of descending commissural interneurons (dCINs) in the hindlimb CPG of the neonatal rat, as well as the role of Ephrin receptor A4 (EphA4) and its Ephrin ligand B3 (EphrinB3), in the construction of the mammalian locomotor network. These latter experiments have defined EphA4 as a molecular marker for mammalian excitatory hindlimb CPG neurons. We also review genetic approaches that can be applied to the mouse spinal cord. These include methods for identifying sub-populations of neurons by genetically encoded reporters, techniques to trace network connectivity with cell-specific genetically encoded tracers, and ways to selectively ablate or eliminate neuron populations from the CPG. We propose that by applying a multidisciplinary approach it will be possible to understand the network structure of the mammalian locomotor CPG. Such an understanding will be instrumental in devising new therapeutic strategies for patients with spinal cord injury.

Animals↗
PubMed2003

Eph receptor deficiencies lead to altered cochlear function.

Ephrins and Eph receptors are a family of molecules that have been implicated in many developmental processes including neuronal network formation, guidance of cell migration, and axonal pathfinding. These molecules exhibit the ability to send bidirectional signals following ligand-receptor interactions resulting from cell-cell contacts. Gene-targeted knockout mice of B-class ephrins and Eph receptors have been shown to display phenotypic responses that correlate with anatomical defects. For example, disruption of the EphB2 receptor leads to defects of the vestibular system, including pathfinding abnormalities in efferent axons and reduced endolymph production. Such developmental distortions lead to deficiencies in ionic homeostasis and repetitive circling behaviors. The present study demonstrates that B-class ephrins and Eph receptors are expressed in cochlear tissues, suggesting that they may play some role in auditory function. To determine whether ephrins and Eph receptors have a functional role in the peripheral auditory system, distortion-product otoacoustic emission (DPOAE) levels, collected across a broad frequency range, were compared between groups of mice expressing different Eph receptor genotypes. In particular, EphB1 and EphB3 receptor knockout mice exhibited significantly diminished DPOAE levels as compared to wild-type littermates, indicating that these specific Eph receptors are necessary for normal cochlear function.

Aging↗
PubMed2001

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.

Age Factors↗
PubMed1999

Eph receptors and ephrins in neural development.

Ephrins, ligands for the Eph family of receptor tyrosine kinases, are pivotal players in many developmental phenomena in both the central and peripheral nervous systems. Ephrins appear to act typically, but not exclusively, as repellents throughout development to influence axon pathfinding and topographic mapping, as well as restricting cell migration and intermingling. Recent findings are beginning to characterize the function and signaling of ephrins, as well as major roles for them in other tissues.

Animals↗
PubMed2003

Hippocampal plasticity requires postsynaptic ephrinBs.

Chemical synapses contain specialized pre- and postsynaptic structures that regulate synaptic transmission and plasticity. EphB receptor tyrosine kinases are important molecular components in this process. Previously, EphB receptors were shown to act postsynaptically, whereas their transmembrane ligands, the ephrinBs, were presumed to act presynaptically. Here we show that in mouse hippocampal CA1 neurons, the Eph/ephrin system is used in an inverted manner: ephrinBs are predominantly localized postsynaptically and are required for synaptic plasticity. We further demonstrate that EphA4, a candidate receptor, is also critically involved in long-term plasticity independent of its cytoplasmic domain, suggesting that ephrinBs are the active signaling partner. This work raises the intriguing possibility that depending on the type of synapse, Eph/ephrins can be involved in activity-dependent plasticity in converse ways, with ephrinBs on the pre- or the postsynaptic side.

Animals↗
PubMed2003

Mouse ephrinB3 augments T-cell signaling and responses to T-cell receptor ligation.

Ephrins (EFN) are cell-surface ligands of Ephs, the largest family of cell-surface receptor tyrosine kinases. The function of EFNs in the immune system has not been well studied, although some EFNs and Ephs are expressed at high levels on certain leukocytes. We report here that EFNB3 and its receptors (collectively called EFNB3Rs, as EFNB3 binds to multiple EphBs) were expressed in peripheral T cells and monocytes/macrophages, with T cells being the dominant EFNB3+ and EFNB3R+ cell type. Solid-phase EFNB3-Fc in the presence of suboptimal anti-CD3 crosslinking enhanced T-cell responses in terms of proliferation, activation marker expression, interferon-gamma but not interleukin-2 production, and cytotoxic T-cell activity. EFNB3R costimulation in the presence of phorbol 12-myristate 13- acetate was insensitive to cyclosporin A, similar to CD28 costimulation, suggesting they might share a part of the signaling pathway. After crosslinking, T-cell receptor and EFNB3R congregated into aggregated rafts, and this provided a morphological basis for signaling pathways of T-cell receptor and EFNB3R to interact. Solid-phase EFNB3-Fc augmented p38 and p44/42 MAPK activation further downstream of the signaling pathway. These data suggest that EFNB3 is important in T-cell/T-cell and T-cell/antigen-presenting cell collaboration to enhance T-cell activation and function.

Animals↗
PubMed2004

Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.

Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS.

Amino Acid Sequence↗
PubMed2003

Role of EphA4 and EphrinB3 in local neuronal circuits that control walking.

Local circuits in the spinal cord that generate locomotion are termed central pattern generators (CPGs). These provide coordinated bilateral control over the normal limb alternation that underlies walking. The molecules that organize the mammalian CPG are unknown. Isolated spinal cords from mice lacking either the EphA4 receptor or its ligand ephrinB3 have lost left-right limb alternation and instead exhibit synchrony. We identified EphA4-positive neurons as an excitatory component of the locomotor CPG. Our study shows that dramatic locomotor changes can occur as a consequence of local genetic rewiring and identifies genes required for the development of normal locomotor behavior.

Animals↗
PubMed1998

The ephrins and Eph receptors in neural development.

The Eph receptors are the largest known family of receptor tyrosine kinases. Initially all of them were identified as orphan receptors without known ligands, and their specific functions were not well understood. During the past few years, a corresponding family of ligands has been identified, called the ephrins, and specific functions have now been identified in neural development. The ephrins and Eph receptors are implicated as positional labels that may guide the development of neural topographic maps. They have also been implicated in pathway selection by axons, the guidance of cell migration, and the establishment of regional pattern in the nervous system. The ligands are anchored to cell surfaces, and most of the functions so far identified can be interpreted as precise guidance of cell or axon movement. This large family of ligands and receptors may make a major contribution to the accurate spatial patterning of connections and cell position in the nervous system.

Animals↗
PubMed2003

Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin.

Eph receptor tyrosine kinases and their ligands, the ephrins, have been primarily described in the nervous system for their roles in axon guidance, development, and cell intermingling. Here we address whether Eph receptors may also regulate dendritic cell (DC) trafficking. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that DCs derived from CD34+ progenitors, but not from monocytes, expressed several receptors, in particular EphA2, EphA4, EphA7, EphB1, and EphB3 mRNA. EphB3 was specifically expressed by Langerhans cells, and EphA2 and EphA7 were expressed by both Langerhans- and interstitial-type DCs. EphA and EphB protein expression on DCs generated in vitro was confirmed by staining with ephrin-A3-Fc and ephrin-B3-Fc fusion proteins that bind to different Eph members, in particular EphA2 and EphB3. Immunostaining with anti-EphA2 antibodies demonstrated the expression of EphA2 by immature DCs and by skin Langerhans cells isolated ex vivo. Interestingly, ephrin expression was detected in epidermal keratinocytes and also in DCs. Adhesion of CD34+-derived DCs to fibronectin, but not to poly-l-lysine, was increased in the presence of ephrin-A3-Fc, a ligand of EphA2, through a beta1 integrin activation pathway. As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking.

Antigens, CD34↗
PubMed2004

A stochastic model for retinocollicular map development.

BACKGROUND: We examine results of gain-of-function experiments on retinocollicular maps in knock-in mice [Brown et al. (2000) Cell 102:77]. In wild-type mice the temporal-nasal axis of retina is mapped to the rostral-caudal axis of superior colliculus. The established map is single-valued, which implies that each point in retina maps to a unique termination zone in superior colliculus. In homozygous Isl2/EphA3 knock-in mice the map is double-valued, which means that each point on retina maps to two termination zones in superior colliculus. This is because about 50 percent of cells in retina express Isl2, and two types of projections, wild-type and Isl2/EphA3 positive, form two branches of the map. In heterozygous Isl2/EphA3 knock-ins the map is intermediate between the homozygous and wild-type: it is single-valued in temporal and double-valued in the nasal parts of retina. In this study we address possible reasons for such a bifurcation of the map. RESULTS: We study the map formation using stochastic model based on Markov chains. In our model the map undergoes a series of reconstructions with probabilities dependent upon a set of chemical cues. Our model suggests that the map in heterozygotes is single-valued in temporal region of retina for two reasons. First, the inhomogeneous gradient of endogenous receptor in retina makes the impact of exogenous receptor less significant in temporal retina. Second, the gradient of ephrin in the corresponding region of superior colliculus is smaller, which reduces the chemical signal-to-noise ratio. We predict that if gradient of ephrin is reduced by a genetic manipulation, the single-valued region of the map should extend to a larger portion of temporal retina, i.e. the point of transition between single-and double-valued maps should move to a more nasal position in Isl2-EphA3 heterozygotes. CONCLUSIONS: We present a theoretical model for retinocollicular map development, which can account for intriguing behaviors observed in gain-of-function experiments by Brown et al., including bifurcation in heterozygous Isl2/EphA3 knock-ins. The model is based on known chemical labels, axonal repulsion/competition, and stochasticity. Possible mapping in Isl2/EphB knock-ins is also discussed.

Animals↗
PubMed2000

The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis.

The cues and signaling systems that guide the formation of embryonic blood vessels in tissues and organs are poorly understood. Members of the Eph family of receptor tyrosine kinases and their cell membrane-anchored ligands, the ephrins, have been assigned important roles in the control of cell migration during embryogenesis, particularly in axon guidance and neural crest migration. Here we investigated the role of EphB receptors and their ligands during embryonic blood vessel development in Xenopus laevis. In a survey of tadpole-stage Xenopus embryos for EphB receptor expression, we detected expression of EphB4 receptors in the posterior cardinal veins and their derivatives, the intersomitic veins. Vascular expression of other EphB receptors, including EphB1, EphB2 or EphB3, could however not be observed, suggesting that EphB4 is the principal EphB receptor of the early embryonic vasculature of Xenopus. Furthermore, we found that ephrin-B ligands are expressed complementary to EphB4 in the somites adjacent to the migratory pathways taken by intersomitic veins during angiogenic growth. We performed RNA injection experiments to study the function of EphB4 and its ligands in intersomitic vein development. Disruption of EphB4 signaling by dominant negative EphB4 receptors or misexpression of ephrin-B ligands in Xenopus embryos resulted in intersomitic veins growing abnormally into the adjacent somitic tissue. Our findings demonstrate that EphB4 and B-class ephrins act as regulators of angiogenesis possibly by mediating repulsive guidance cues to migrating endothelial cells.

Animals↗
PubMed1999

High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.

Neuroblastoma (NB) is a common pediatric tumor of neural crest origin that is biologically and clinically heterogeneous. EPH family receptor tyrosine kinases and ephrin ligands play fundamental roles in neurodevelopmental processes. Recently, we found that NB cell lines expressed several EPHB and EFNB transcripts, which encode EPHB subgroup receptors and ephrin-B subgroup ligands, respectively. To explore the role of EPHB receptors and ephrin-B ligands in the biology of NB, we examined the expression of EPHB and EFNB transcripts in 47 primary NB specimens. Multiple EPHB and EFNB transcripts were expressed in all of the NB tumors examined, suggesting the involvement of these transcripts in modulating the biological behavior of NB. Higher levels of EPHB6, EFNB2, and EFNB3 expression were found in low-stage tumors (stage 1, 2, and 4S) than in advanced-stage tumors (stage 3 and 4; P = 0.0013, P = 0.0048, and P = 0.027, respectively). Expression of TrkA, a well-established prognostic marker of favorable NB, was positively correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.0001, P = 0.0019, and P = 0.0001, respectively). MYCN-amplified tumors expressed lower levels of EPHB6, EFNB2, EFNB3, and TrkA transcripts compared to nonamplified tumors (P = 0.0006, P = 0.0023, P = 0.0048, and P = 0.0001, respectively). These data suggest that high-level expression of EPHB6, EFNB2, and EFNB3 is associated with favorable NB and that low-level expression of EPHB6, EFNB2, and EFNB3 correlates with aggressive MYCN-amplified NB. Thus, EPHB6, EFNB2, and EFNB3 may have biological relevance in NB. Further investigation on the biology of these genes may help provide insight into the treatment of NB.

Ephrin-B2↗
PubMed2000

[Involvement of ephrins and their receptors in oncogenesis].

Ephrins are membrane-linked ligands with an autocrine and/or immediate paracrine action. Ephrins were previously involved in embryonic neurogenesis, axonal guidance and/or retraction. Here, we will present data of the literature describing their roles in angiogenesis and in tumor progression. The capacity for ephrins to act in opposite directions will be discussed.

Animals↗