Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling

Himanen, Juha P.; Chumley, Michael J.; Lackmann, Martin; Li, Chen; Barton, William A.; Jeffrey, Philip D.; Vearing, Christopher; Geleick, Detlef; Feldheim, David A.; Boyd, Andrew W.; Henkemeyer, Mark; Nikolov, Dimitar B.

doi:10.1038/nn1237

Cited by 410 publications

(365 citation statements)

References 38 publications

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“…Thus, it is tempting to speculate that EphA4 is the partner of ephrin-A5 in this repulsive/permissive system. In contrast, EphB2, although known to interact with ephrin-A5 16 , does not seem to be a good candidate, as it is equally expressed in both type I and type II SGNs.…”

Section: Discussionmentioning

confidence: 92%

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

et al. 2013

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Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.

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Section: Discussionmentioning

confidence: 92%

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

et al. 2013

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“…4). Although it is classically believed that EphA and EphB receptors interact solely with ephrin-A and ephrin-B ligands, respectively, recent work has demonstrated crosstalk between these ephrin subfamilies (Himanen et al, 2004). Future work will be necessary to determine the roles of ephrin-B1 and Eph-A2 in mammary development and to evaluate potential crosstalk between these cell-surface proteins.…”

Section: Ephrin Expressionmentioning

confidence: 99%

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

Kouros-Mehr¹,

Werb

2006

Developmental Dynamics

201

177

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The mammary gland develops in a process known as branching morphogenesis, whereby a distal epithelial bud extends and bifurcates to form an extensive ductal network. Compared with other branched organs, such as the lung and kidney, little is known about the molecular basis of branching in the mammary gland. Here we report a microarray profiling strategy to identify novel genes that may regulate mammary branching. We microdissected terminal end bud (TEB) and mature duct microenvironments from ␤-actin-green fluorescent protein reporter mice and compared their RNA expression profiles with epithelium-free mammary stroma by means of microarray. We identified 1,074 genes enriched in the TEB microenvironment, 222 genes enriched in the mature duct microenvironment, and 385 genes enriched in both TEB and mature duct microenvironments. The microarray correctly predicted the expression of genes known to be enriched in the epithelium (Ets-5) and stroma (MMP-14) of TEBs and in the mature duct microenvironment (MMP-3). The microarray also correctly predicted the localization of previously uncharacterized genes, such as the TEB-enriched SPRR-1a, the duct-enriched casein-␥, and the general epithelial marker pleiotrophin. Analysis of genes enriched in TEBs revealed several genes in the Wnt (Wnt-2, Wnt-5a, Wnt-7b, Dsh-3, Frizzled-1, Frizzled-2), hedgehog (Dhh), ephrin (Ephrin-B1, Eph-A2), and transcription factor (Twist-1, Twist-2, Snail) families. In situ hybridization verified that these genes were enriched in the TEB epithelium (Wnt-5a, Wnt-7b, Dhh, Eph-A2) or TEB stroma (Wnt-2, Frizzled-1, Ephrin-B1). We discuss the potential roles of these genes in mammary branching morphogenesis. Developmental Dynamics 235:3404 -3412, 2006.

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“…EphrinA and B differ in their membrane-anchorage and on their receptor affinity: ephrinA are glycosylphosphatidylinositol (GPI)-linked proteins and bind generally to the EphA-receptors, whereas ephrinB have a transmembrane domain and a cytoplasmic region, and interact preferentially with EphB-receptors. Exceptions in the binding discrimination between classes are that ephrinA5, at high concentration, can bind to EphB2 [6], and ephrinB-ligands to EphA4 [7]. Ephrins and their receptors are highly expressed in the developing nervous system and often in complementary gradients inside delimited regions of the central nervous system [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Within the ephrinA group, ephrinA5 has been extensively studied and was shown to be a ligand for EphA3 [11,12], EphA4 [13,14], EphA5 [10], EphA7 [15] and EphB2 [6] receptors. The study of its expression, mainly explored at the mRNA level in the rodent developing brain, has shown that ephrinA5 is present from early organogenesis [16] to postnatal stages throughout the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

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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Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling

Cited by 410 publications

References 38 publications

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

Candidate regulators of mammary branching morphogenesis identified by genome‐wide transcript analysis

EphrinA5 protein distribution in the developing mouse brain

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