Modulation of EphA Receptor Function by Coexpressed EphrinA Ligands on Retinal Ganglion Cell Axons

Hornberger, Martin R.; Dütting, Dieter; Ciossek, Thomas; Yamada, Tomoko; Handwerker, Claudia; Lang, Susanne; Weth, Franco; Huf, Julita; Weßel, Ralf; Logan, Cairine; Tanaka, Hideaki; Drescher, Uwe

doi:10.1016/s0896-6273(00)80732-1

Cited by 348 publications

(265 citation statements)

References 36 publications

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“…We investigated ephrinA5 protein expression in the retina and detected a high expression in the nasal part compared to the temporal one. This result is in accordance with the previously described retinal ephrinA5 expression pattern in the chick [51] and with ephrinA5 mRNA expression found in a high-nasal-to-low-temporal gradient in the developing mouse embryo retina [52]. As previously described, the mouse retinal ganglion cells also expressed EphA5 and EphA6 receptors [53].…”

Section: Discussionsupporting

confidence: 92%

“…However, it is unlikely that the co-expression of ligand and receptor in the same region of the visual system is responsible of an attractive mechanism, since it has been extensively shown, using in vitro studies and double ephrinA2/ephrinA5 knock-out mice [30,48-50], that the topographic map of the visual system is established by a chemorepellent activity of ephrinAs [50]. Nevertheless, it may be that ligands and receptors are present on the same cells, as it has been shown in the chick retinal ganglion cells, where ephrinA2, ephrinA5 and EphA5 mRNA are co-expressed [51]. In this case, the presence of ephrinA-ligand on the retinal ganglion cells could control the EphA-receptor function through a modulation of its intracellular signalling pathway [51] as discussed above.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, it may be that ligands and receptors are present on the same cells, as it has been shown in the chick retinal ganglion cells, where ephrinA2, ephrinA5 and EphA5 mRNA are co-expressed [51]. In this case, the presence of ephrinA-ligand on the retinal ganglion cells could control the EphA-receptor function through a modulation of its intracellular signalling pathway [51] as discussed above.…”

Section: Discussionmentioning

confidence: 99%

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EphrinA5 protein distribution in the developing mouse brain

Deschamps¹,

Morel²,

Janet³

et al. 2010

BMC Neurosci

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Background EphrinA5 is one of the best-studied members of the Eph-ephrin family of guidance molecules, known to be involved in brain developmental processes. Using in situ hybridization, ephrinA5 mRNA expression has been detected in the retinotectal, the thalamocortical, and the olfactory systems; however, no study focused on the distribution of the protein. Considering that this membrane-anchored molecule may act far from the neuron soma expressing the transcript, it is of a crucial interest to localize ephrinA5 protein to better understand its function. Results Using immunohistochemistry, we found that ephrinA5 protein is highly expressed in the developing mouse brain from E12.5 to E16.5. The olfactory bulb, the cortex, the striatum, the thalamus, and the colliculi showed high intensity of labelling, suggesting its implication in topographic mapping of olfactory, retinocollicular, thalamocortical, corticothalamic and mesostriatal systems. In the olfactory nerve, we found an early ephrinA5 protein expression at E12.5 suggesting its implication in the guidance of primary olfactory neurons into the olfactory bulb. In the thalamus, we detected a dynamic graduated protein expression, suggesting its role in the corticothalamic patterning, whereas ephrinA5 protein expression in the target region of mesencephalic dopaminergic neurones indicated its involvement in the mesostriatal topographic mapping. Following E16.5, the signal faded gradually and was barely detectable at P0, suggesting a main role for ephrinA5 in primary molecular events in topographic map formation. Conclusion Our work shows that ephrinA5 protein is expressed in restrictive regions of the developing mouse brain. This expression pattern points out the potential sites of action of this molecule in the olfactory, retinotectal, thalamocortical, corticothalamic and mesostriatal systems, during development. This study is essential to better understand the role of ephrinA5 during developmental topographic mapping of connections and to further characterise the mechanisms involved in pathway restoration following cell transplantation in the damaged brain.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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EphrinA5 protein distribution in the developing mouse brain

Deschamps¹,

Morel²,

Janet³

et al. 2010

BMC Neurosci

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“…Surprisingly though, different Eph receptors and ephrins are often co-expressed by the same cells raising the question about potential interactions in cis (within the same cell) affecting the functional signaling in trans (between the opposing cells). The in-cis-interaction theory gained momentum after several reports indicated that the responsiveness of EphA expressing retinal axons is negatively modulated by A-class ligands expressed on the same cells [43,44]. Interestingly, a seemingly contradictory conclusion was published by Marquardt, Pfaff and colleagues [45], who documented that at least in spinal motor neurons coexpressed Ephs and ephrins segregate laterally into distinct membrane domains from which they induce opposing effects: EphAs direct growth cone collapse/repulsion, while ephrin-As signal motor axon growth/attraction.…”

Section: Eph/ephrin Interactions On the Surface Of The Same Cellmentioning

confidence: 99%

Cell–cell signaling via Eph receptors and ephrins

Himanen

Saha

Nikolov

2007

Current Opinion in Cell Biology

225

202

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SummaryEph receptors are the largest subfamily of receptor tyrosine kinases regulating cell shape, movements and attachment. The interactions of the Ephs with their ephrin ligands are restricted to the sites of cell-cell contact since both molecules are membrane attached. This review summarizes recent advances in our understanding of the molecular mechanisms underlining the diverse functions of the molecules during development and in the adult organism. The unique properties of this signaling system that are of highest interest and have been the focus of intense investigations are as follows: (i) the signal is often simultaneously transduced in both ligand-and receptor-expressing cells, (ii) signaling via the same molecules can generate opposing cellular reactions depending on the context, and (iii) the Ephs and the ephrins are divided in two subclasses with promiscuous intra-subclass interactions, but rarely observed inter-subclass interactions.

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“…This protocol was adapted by various research groups for their experimental designs and, for these modifications, we would like to refer throughout the manuscript to the relevant primary research literature 5,6,9,10,14,18,33 . First we describe the guidance behavior of axons from chick retinal ganglion cells (RGCs) growing on carpets consisting of alternating membrane fractions derived from anterior and posterior chick optic tecta (original version, Step 1A of PROCEDURE).…”

Section: Introductionmentioning

confidence: 99%

Stripe assay to examine axonal guidance and cell migration

et al. 2007

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Stripe assays have been widely employed as in vitro test systems to study the responses of growing axons, as well as migrating cells, to established or novel guidance molecules. We provide detailed protocols for both the original and the modified version of this assay, as they allow the analysis of the 'guidance properties' of active components present in crude membrane fractions or as purified molecules. Silicon matrices are used to produce striped patterns of active molecules on a surface (referred to as 'carpet'), followed by culturing of neurons, or any other cell type, on these carpets. After 1-2 days in culture, striped outgrowth of extending neuritesindicative of guided migration of cell processes-can be observed. We also discuss potential other applications (e.g., in neuronal regeneration and development) and modifications of the assay. The preparation of 10-12 carpets takes approximately 4-5 h. INTRODUCTIONThe stripe assay was originally designed by F. Bonhoeffer and co-workers 1,2 in the late 1980s to analyze fundamental axonal guidance mechanisms governing the formation of the topographic map established in the chick retino-tectal system (for review, see ref.3). Employing this assay, the presence of a graded distribution of repulsive axon guidance cues, present predominantly in posterior tectal membranes, was discovered. Subsequently, this assay was modified, permitting the identification of ephrin-As as the key components present in posterior membranes that are responsible for the repulsive properties 4-7 .The stripe assay has since been used to uncover guidance cues and mechanisms in many principal neuronal projections, including, for example, the hippocampal, thalamic and olfactory systems [8][9][10][11] . The stripe assay was also applied to investigate neurite outgrowth and guidance behavior related to neuronal regeneration 12-15 and branch formation 16 . Furthermore, the stripe assay has proven valuable in dissecting signaling cascades initiated downstream of axonal guidance receptors activated by ligands printed in a striped pattern [12][13][14][15] . In addition, the guidance properties of membrane-tethered molecules as well as the short-range action of secreted guidance molecules (such as Slits and Semaphorins) could be mimicked in vitro by this assay 17,18 . Also stripe assay experiments were conducted to unravel potential guidance properties of extracellular matrix components 19,20 and of cell adhesion molecules of the IgG superfamily 21 .Of note, the stripe assay was employed as an in vitro assay to investigate the navigation responses of both axonal growth cones toward guidance cues and of migrating cells 4,22,23 . With respect to the latter, neural crest cells 22 and oligodendrocytes 23,24 , but also non-neuronal cells such as tumor cells, have been studied 25 .The assay allows assessment of guidance activity of established molecules and also testing potential guidance properties of hitherto uncharacterized molecules such as RGM, the Wnt signaling inhibitor SFRP1 or the morphogen Sonic h...

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Modulation of EphA Receptor Function by Coexpressed EphrinA Ligands on Retinal Ganglion Cell Axons

Cited by 348 publications

References 36 publications

EphrinA5 protein distribution in the developing mouse brain

EphrinA5 protein distribution in the developing mouse brain

Cell–cell signaling via Eph receptors and ephrins

Stripe assay to examine axonal guidance and cell migration

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