Regulation of EphA4 Kinase Activity Is Required for a Subset of Axon Guidance Decisions Suggesting a Key Role for Receptor Clustering in Eph Function

Egea, Joaquim; Nissen, Ulla Vig; Dufour, Audrey; Şahin, Mustafa; Greer, Paul L.; Kullander, Klas; Mrsic-Flogel, Thomas D.; Greenberg, Michael E.; Kiehn, Ole; Vanderhaeghen, Pierre; Klein, Rüdiger

doi:10.1016/j.neuron.2005.06.029

Cited by 108 publications

(101 citation statements)

References 41 publications

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“…The long fasciculated corticospinal tract develops normally in ephrinB3 −/− mice, but segmental corticospinal tract (CST) projections cross the midline inappropriately after leaving the bundled dorsalCST, before reaching caudal synaptic targets. However, the abnormal bilateral synchronization of hindlimb gait observed in ephrinB3 −/− mice does not depend on misrouted CST fibers but reflects excess midline crossing of EphA4-expressing segmental interneurons of the central locomotor pattern generator in the spinal cord (27)(28)(29).…”

Section: Neurology | Locomotionmentioning

confidence: 96%

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Duffy

Wang

Siegel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Recovery of neurological function after traumatic injury of the adult mammalian central nervous system is limited by lack of axonal growth. Myelin-derived inhibitors contribute to axonal growth restriction, with ephrinB3 being a developmentally important axonal guidance cue whose expression in mature oligodendrocytes suggests a role in regeneration. Here we explored the in vivo regeneration role of ephrinB3 using mice lacking a functional ephrinB3 gene. We confirm that ephrinB3 accounts for a substantial portion of detergent-resistant myelin-derived inhibition in vitro. To assess in vivo regeneration, we crushed the optic nerve and examined retinal ganglion fibers extending past the crush site. Significantly increased axonal regeneration is detected in ephrinB3 −/− mice. Studies of spinal cord injury in ephrinB3 −/− mice must take into account altered spinal cord development and an abnormal hopping gait before injury. In a near-total thoracic transection model, ephrinB3 −/− mice show greater spasticity than wild-type mice for 2 mo, with slightly greater hindlimb function at later time points, but no evidence for axonal regeneration. After a dorsal hemisection injury, increased corticospinal and raphespinal growth in the caudal spinal cord are detected by 6 wk. This increased axonal growth is accompanied by improved locomotor performance measured in the open field and by kinematic analysis. Thus, ephrinB3 contributes to myelin-derived axonal growth inhibition and limits recovery from adult CNS trauma.

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Section: Neurology | Locomotionmentioning

confidence: 96%

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Duffy

Wang

Siegel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…PC12 cells were obtained from Dr. Brian B. Rudkin (Lyon, France). This cell line was cultured as described previously (Egea et al, 2005). For experiments, PC12 cells were seeded in polyornithine-precoated 100 mm Petri dishes and left to adhere.…”

Section: Methodsmentioning

confidence: 99%

A TrkB/EphrinA Interaction Controls Retinal Axon Branching and Synaptogenesis

Marler¹,

Becker-Barroso²,

Martı́nez³

et al. 2008

J. Neurosci.

148

176

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Toward understanding topographically specific branching of retinal axons in their target area, we have studied the interaction between neurotrophin receptors and members of the Eph family. TrkB and its ligand BDNF are uniformly expressed in the retina and tectum, respectively, and exert a branch-promoting activity, whereas EphAs and ephrinAs are expressed in gradients in retina and tectum and can mediate a suppression of axonal branching. We have identified a novel cis interaction between ephrinA5 and TrkB on retinal ganglion cell axons. TrkB interacts with ephrinA5 via its second cysteine-rich domain (CC2), which is necessary and sufficient for binding to ephrinA5. Their functional interaction is twofold: ephrinA5 augments BDNF-promoted retinal axon branching in the absence of its activator EphA7-Fc, whereas EphA7-Fc application abolishes branching in a local and concentration-dependent manner. The importance of TrkB in this process is shown by the fact that overexpression of an isolated TrkB-CC2 domain interfering with the ephrinA/TrkB interaction abolishes this regulatory interplay, whereas knockdown of TrkB via RNA interference diminishes the ephrinA5-evoked increase in branching. The ephrinA/Trk interaction is neurotrophin induced and specifically augments the PI-3 kinase/Akt pathway generally known to be involved in the promotion of branching. In addition, ephrinAs/TrkB modulate axon branching and also synapse formation of hippocampal neurons. Our findings uncover molecular mechanisms of how spatially restricted axon branching can be achieved by linking globally expressed branch-promoting with differentially expressed branch-suppressing activities. In addition, our data suggest that growth factors and the EphA-ephrinA system interact in a way that affects axon branching and synapse development.

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“…The membrane-bound ephrin ligands require cell-cell contact and multimeric engagement for full signaling activity (Davis et al, 1994;Stein et al, 1998;Egea et al, 2005). The final vascular response to ephrinB2 engagement with its receptors on adjacent cells is shaped by bidirectional signaling interactions within endothelial populations and between endothelial cells and adjacent nonendothelial populations (Heroult et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

Wilkinson

Schittny

Reinhardt

et al. 2008

Developmental Dynamics

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Alveoli are formed in the lung by the insertion of secondary tissue folds, termed septa, which are subsequently remodeled to form the mature alveolar wall. Secondary septation requires interplay between three cell types: endothelial cells forming capillaries, contractile interstitial myofibroblasts, and epithelial cells. Here, we report that postnatal lung alveolization critically requires ephrinB2, a ligand for Eph receptor tyrosine kinases expressed by the microvasculature. Mice homozygous for the hypomorphic knockin allele ephrinB2 ⌬V/⌬V , encoding mutant ephrinB2 with a disrupted C-terminal PDZ interaction motif, show severe postnatal lung defects including an almost complete absence of lung alveoli and abnormal and disorganized elastic matrix. Lung alveolar formation is not sensitive to loss of ephrinB2 cytoplasmic tyrosine phosphorylation sites. Postnatal day 1 mutant lungs show extracellular matrix alterations without differences in proportions of major distal cell populations. We conclude that lung alveolar formation relies on endothelial ephrinB2 function. Developmental Dynamics 237:2220 -2234, 2008.

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Regulation of EphA4 Kinase Activity Is Required for a Subset of Axon Guidance Decisions Suggesting a Key Role for Receptor Clustering in Eph Function

Cited by 108 publications

References 41 publications

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

A TrkB/EphrinA Interaction Controls Retinal Axon Branching and Synaptogenesis

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

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