The interaction between ephrin ligands (efn) and their receptors (Eph) is capable of inducing forward signaling, from ligand to receptor, as well as reverse signaling, from receptor to ligand. The ephrins are widely expressed in many tissues, where they mediate cell migration and adherence, properties that make the efn-Eph signaling critically important in establishing and maintaining tissue boundaries. The efn-Eph system has also received considerable attention in skeletal tissues, as ligand and receptor combinations are predicted to mediate interactions between the different types of cells that regulate bone development and homeostasis. This review summarizes our current understanding of efn-Eph signaling with a particular focus on the expression and functions of ephrins and their receptors in bone.
Bone Development ; Cell Movement ; Ephrins ; Homeostasis ; Ligands ; Osteoblasts ; Osteoclasts

Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system. Interestingly, the chemotactic properties of AGMs are also important in the postnatal period, such as in the regulation of immune and inflammatory responses. In particular, AGMs play pivotal roles in inflammation of the nervous system, by either stimulating or inhibiting inflammatory responses, depending on specific ligand-receptor combinations. Understanding such regulatory functions of AGMs in neuroinflammation may allow finding new molecular targets to treat neurodegenerative diseases, in which neuroinflammation underlies aetiology and progression.
Axons ; Ephrins ; Inflammation ; Nervous System ; Neurodegenerative Diseases ; Neuroglia ; Semaphorins

BACKGROUNDIn a previous study, we demonstrated that ephrin-A2 and -A3 negatively regulate the growth of neural progenitor cells in the central nervous system. Adult mice deficient in ephrin-A2 and -A3 (A2(-/-)A3(-/-)) displayed active ongoing neurogenesis throughout the brain, and mice deficient in ephrin-A3 alone showed increased proliferation of ciliary epithelium derived retinal stem cells. This study aimed to detect that the increase in proliferation and neurogenic potential of Müller cells is influenced by the absence of ephrin-A2 and -A3.

METHODSWe assessed the retinal and Müller cell expression of ephrin-As and their receptor and neural progenitor cell markers by immunostaining and real-time PCR. We cultured purified primary Müller cells derived from wild-type and A2(-/-)A3(-/-) mice in a defined culture medium that enables trans-differentiation of Müller cells into retinal neurons. To evaluate proliferating Müller cells in vivo, we injected 5'-ethylnyl-2'-deoxiuridine (EdU) intraperitoneally to adult mice.

RESULTSExpression of ephrin-A2/A3 and their receptor EphA4 were detected in the retinas of adult mice, with EphA4 expression particularly enriched in Müller cells. Müller cells of A2(-/-)A3(-/-) mice exhibited significantly elevated expression of retinal progenitor cell markers, Pax6 and Chx10, when compared with those from wild-type mice. Moreover, a higher percentage of Müller cells of A2(-/-)A3(-/-) mice trans-differentiated and became recoverin+ and β-III-tublin+ in the culture than those from wild type mice. Strikingly, an increased number of EdU+ retinal cells was detected in the retinas of adult A2(-/-)A3(-/-) mice as compared with wild-type mice.

CONCLUSIONSEphrin-A2 and -A3 are negative regulators of the proliferative and neurogenic potentials of Müller cells. Manipulating ephrin-A signaling may thus represent a novel strategy for stimulating neuroregeneration from endogenous progenitors to participate in retinal repair in case of disease or damage.

Animals ; Cell Differentiation ; genetics ; physiology ; Ephrin-A2 ; genetics ; metabolism ; Ephrin-A3 ; genetics ; metabolism ; Fluorescent Antibody Technique ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Real-Time Polymerase Chain Reaction ; Receptor, EphA4 ; genetics ; metabolism ; Retina ; cytology ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Stem Cells ; cytology ; metabolism

Eph receptors and their ligands, ephrins, are abundantly expressed in neuroepithelial cells of the early embryonic brain. Overstimulation of Eph signaling in vivo increases apoptotic cell death of neuroepithelial cells, whereas null mutation of the Eph gene leads to the development of a larger brain during embryogenesis. Thus, it appears that Eph-ephrin signaling plays a role in regulating apoptotic cell death of neuroepithelial cells, thereby influencing brain size during embryonic development. Interestingly, Eph-ephrin signaling is bi-directional, with forward signaling from ephrin- to Eph-expressing cells and reverse signaling from Eph- to ephrin-expressing cells. However, it is not clear whether this forward or reverse signaling plays a role in regulating the size of the neuroepithelial cell population during early brain development. Also, Eph receptors and their corresponding ligands are mutually exclusive in their expression domains, and they encounter each other only at interfaces between their expression domains. This expression pattern may be a critical mechanism for preventing overstimulation of Eph-ephrin signaling. Nevertheless, Eph receptors are co-expressed with their corresponding ligands in certain brain regions. Recently, two studies demonstrated that brain region-specific apoptosis may be triggered by the overlapping expression of Eph and ephrin, a theme that will be explored in this mini-review.
Apoptosis ; Brain ; Cell Death ; Embryonic Development ; Ephrins ; Female ; Ligands ; Neuroepithelial Cells ; Pregnancy ; Receptor, EphA1 ; Receptors, Eph Family

Objective To investigate the effects of different inflammatory factors on hepatocyte kinase receptor(Eph)and ligand(ephrin)in human periodontal ligament fibroblasts(hPDLFs).Methods hPDLFs were stimulated with either 10 ng/ml tumor necrosis factor-α(TNF-α)or 10 ng/ml interleukin(IL)-1β,and then the expressions of Eph and ephrin at both mRNA and protein levels were determined at 0,1,2,6,12,and 24 hours.Results The levels of Eph receptors and ephrin ligand changed in a time-dependent manner in human periodontal ligament fibroblasts after treatment with TNF-α or IL-1β. The expression of ephrinA2 significantly increased in both groups within 24 hours(all <0.05). In the TNF-α group,the mRNA expression of ephrinA2 significantly increased at 1 h and was significant higher that in the IL-1β group at 24 h(<0.05). EphB4 showed a time-dependent decline after a short period of high expression.Conclusions Both TNF-α and IL-1β can cause changes in the expressions of Eph receptors and ephrin ligands in hPDLFs. The changes induced by both are consistent,although the effect of TNF-α is more pronounced.
Cells, Cultured ; Ephrins ; metabolism ; Fibroblasts ; Humans ; Interleukin-1beta ; pharmacology ; Ligands ; Periodontal Ligament ; cytology ; Receptors, Eph Family ; metabolism ; Tumor Necrosis Factor-alpha ; pharmacology

Neuropathic pain is a complex chronic pain state caused by the dysfunction of somatosensory nervous system, and it affects the millions of people worldwide. At present, there are very few medical treatments available for neuropathic pain management and the intolerable side effects of medications may further worsen the symptoms. Despite the presence of profound knowledge that delineates the pathophysiology and mechanisms leading to neuropathic pain, the unmet clinical needs demand more research in this field that would ultimately assist to ameliorate the pain conditions. Efforts are being made globally to explore and understand the basic molecular mechanisms responsible for somatosensory dysfunction in preclinical pain models. The present review highlights some of the novel molecular targets like D-amino acid oxidase, endoplasmic reticulum stress receptors, sigma receptors, hyperpolarization-activated cyclic nucleotide-gated cation channels, histone deacetylase, Wnt/β-catenin and Wnt/Ryk, ephrins and Eph receptor tyrosine kinase, Cdh-1 and mitochondrial ATPase that are implicated in the induction of neuropathic pain. Studies conducted on the different animal models and observed results have been summarized with an aim to facilitate the efforts made in the drug discovery. The diligent analysis and exploitation of these targets may help in the identification of some promising therapies that can better manage neuropathic pain and improve the health of patients.
Adenosine Triphosphatases ; Chronic Pain ; Cyclic Nucleotide-Gated Cation Channels ; Drug Discovery ; Endoplasmic Reticulum Stress ; Ephrins ; Histone Deacetylases ; Humans ; Models, Animal ; Nervous System ; Neuralgia* ; Oxidoreductases ; Receptors, Eph Family ; Receptors, sigma

With the advances in pre- and post-natal medical care, the incidence of bronchopulmonary dysplasia (BPD) is on the rise, while its pathogenesis remains not clear. New BPD theory shows that the core pathogenesis of BPD is simple alveolar structure and pulmonary microvascular abnormalities that eventually lead to reduced pulmonary gas exchange, so the research on pulmonary microvascular development was gradually taken seriously. Pulmonary angiogenesis and vascular development require the participation of various cytokines and signaling pathways, the most important of which include VEGF/VEGFR pathway, Ang/Tie pathway, Ephrins/Eph pathway, and Notch/Jagged1 pathway. These cytokines and signaling pathways play important roles in pulmonary vascular development.
Angiopoietins ; physiology ; Blood Vessels ; embryology ; Bronchopulmonary Dysplasia ; etiology ; Cytokines ; physiology ; Ephrins ; physiology ; Humans ; Infant, Newborn ; Lung ; blood supply ; Neovascularization, Physiologic ; Receptors, Notch ; physiology ; Signal Transduction ; physiology ; Vascular Endothelial Growth Factor A ; physiology

EphA/ephrin-A mediated signaling has emerged as a key mechanism regulating axon guidance and topographic mapping, particularly in the well-characterized visual system from the retina to the superior colliculus (SC). In this study, EphA8 bacterial artificial chromosome (BAC) was manipulated to contain a floxed eGFP and human ephrin-A5 expression cassette using homologous recombination method. In the mice containing the recombinant BAC, it was shown that GFP is expressed in an anterior>posterior gradient in the SC. Furthermore, when these mice were crossed with the transgenic mice expressing Cre under the EphA8 promoter, it was evident that a GFP expression cassette was eliminated, and that human ephrin-A5 was ectopically expressed in the anterior region of the SC. This transgenic model would be useful to analyze the role of ephrin-A5 in the SC during the retinocollicular topography formation.
Animals ; Axons ; Chromosomes, Artificial, Bacterial ; Ephrin-A5 ; Homologous Recombination ; Humans ; Mice ; Mice, Transgenic ; Retina ; Superior Colliculi

OBJECTIVETo investigate the changes in the expression of EphA5 and its ligand ephrinA5 in the hippocampus of rats with epilepsy and their role in the pathogenesis of temporal lobe epilepsy (TLE).

METHODSA total of 240 Sprague-Dawley rats were randomly divided into control group and TLE group, with 120 rats in each group. A rat model of lithium-pilocarpine TLE was established, and then the rats were divided into subgroups at 12 and 24 hours and 7, 15, 30, and 60 days after epilepsy was induced. In-situ hybridization was used to measure the mRNA expression of ephrinA5 in the CA3 region and the dentate gyrus of the hippocampus in 9 rats; immunohistochemistry was used to measure the protein expression of EphA5 in the CA3 region and the dentate gyrus of the hippocampus in 9 rats; Neo-Timm silver staining was used to observe mossy fiber sprouting in the CA3 region of the hippocampus in 2 rats.

RESULTSIn-situ hybridization showed mRNA expression of ephrinA5 in the CA3 region of the hippocampus, but this was not found in the dentate gyrus. Compared with the control group at the same time point, the TLE group had a significant reduction in the mRNA expression of ephrinA5 in the CA3 region of the hippocampus at 7 and 15 days after epilepsy was induced (P<0.05); at 30 and 60 days after epilepsy was induced, the TLE group had a gradual increase in the mRNA expression of ephrinA5 in the CA3 region of the hippocampus, and there was no significant difference between the TLE and control groups (P>0.05). Immunohistochemistry showed that EphA5 protein was expressed in the CA3 region and the dentate gyrus of the hippocampus and had a similar trend of change as ephrinA5 mRNA. Neo-Timm silver staining showed that the TLE group developed marked mossy fiber sprouting in the CA3 region of the hippocampus at 7 and 15 days after epilepsy was induced.

CONCLUSIONSDownregulation of ephrinA5 and EphA5 in the CA3 region of the hippocampus may participate in the mechanism of mossy fiber sprouting and is closely associated with the development and progression of epilepsy.

Animals ; Ephrin-A5 ; analysis ; genetics ; physiology ; Epilepsy, Temporal Lobe ; etiology ; metabolism ; Hippocampus ; chemistry ; Male ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Receptor, EphA5 ; analysis ; genetics ; physiology

OBJECTIVESTo study the expression patterns of two Eph family molecules, the receptor EphA5, and the ligand ephrin-A5, during spinal cord development.

METHODSThe receptor expression was analyzed using beta-galactosidase knockin mice, and affinity ligand probe binding. The ligand expression was assessed using two different affinity probes, and knockout mouse tissues as controls.

RESULTSEphA5 was expressed in the ventral spinal cord, while ephrin-A5 was located in the dorsolateral regions of the spinal cord throughout development.

CONCLUSIONSThese results show that EphA5 and ephrin-A5 are expressed over broad developmental stages and may play important roles in establishing the dorsoventral organization of the spinal cord.

Animals ; Ephrin-A5 ; biosynthesis ; Gene Expression ; Gene Expression Regulation, Developmental ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Receptor, EphA5 ; biosynthesis ; Spinal Cord ; embryology ; metabolism