EphA4-Dependent Axon Guidance Is Mediated by the RacGAP α2-Chimaerin

Department of Molecular Neurobiology and DFG Center for Molecular Physiology of the Brain, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany.
Neuron (Impact Factor: 15.05). 10/2007; 55(5):756-67. DOI: 10.1016/j.neuron.2007.07.038
Source: PubMed


Neuronal network formation in the developing nervous system is dependent on the accurate navigation of nerve cell axons and dendrites, which is controlled by attractive and repulsive guidance cues. Ephrins and their cognate Eph receptors mediate many repulsive axonal guidance decisions by intercellular interactions resulting in growth cone collapse and axon retraction of the Eph-presenting neuron. We show that the Rac-specific GTPase-activating protein alpha2-chimaerin binds activated EphA4 and mediates EphA4-triggered axonal growth cone collapse. alpha-Chimaerin mutant mice display a phenotype similar to that of EphA4 mutant mice, including aberrant midline axon guidance and defective spinal cord central pattern generator activity. Our results reveal an alpha-chimaerin-dependent signaling pathway downstream of EphA4, which is essential for axon guidance decisions and neuronal circuit formation in vivo.

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    • "It has been demonstrated that Vav3 [Fang et al., 2008] and Ephexin [25] each binds to EphA4, through their plekstrin-homology (PH) domain [Bustelo, 2002; Ogita et al., 2003], for their phosphorylation and activation by the EphA4 PTK catalytic domain. There is also suggestive evidence that Vav3 and Ephexin both bind to the same structural domain of EphA4 that includes the Y596/Y602 residues [Wegmeyer et al., 2007; Takeuchi et al., 2009]. The binding of Vav3 to EphA4 [Fang et al., 2008], but not that of Ephexin to EphA4 [Shamah et al., 2001], requires the phosphorylation of these two juxamemberane tyrosines (i.e., pY596/ pY602). "
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    ABSTRACT: We have previously shown that PTP-oc is an enhancer of the functional activity of osteoclasts and that EphA4 is a suppressor. Here, we provide evidence that PTP-oc enhances osteoclast activity in part through inactivation of EphA4 by dephosphorylating key phosphotyrosine (pY) residues of EphA4. We show that EphA4 was pulled down by the PTP-oc trapping mutant but not by the wild-type (WT) PTP-oc and that transgenic overexpression of PTP-oc in osteoclasts drastically decreased pY602 and pY779 residues of EphA4. Consistent with the previous findings that EphA4 deficiency increased pY173-Vav3 level [Rac-GTP exchange factor (GEF)] and enhanced bone resorption activity of osteoclasts, reintroduction of WT-Epha4 in Epha4 null osteoclasts led to ∼50% reduction in the pY173-Vav3 level and ∼2-fold increase in bone resorption activity. Overexpression of Y779F-Epha4 mutant in WT osteoclasts markedly increased in pY173-Vav3 and reduced bone resorption activity, but overexpression of Y602F-Epha4 mutant had no effect, suggesting that pY779 residue plays an important role in the EphA4-mediated suppression of osteoclast activity. Deficient EphA4 in osteoclasts has been shown to up-regulate Rac-GTPase and down-regulate Rho-GTPase. PTP-oc overexpression in osteoclasts also increased the GTP-Rac level to 300% of controls, but decreased the GTP-Rho level to ∼50% of controls. PTP-oc overexpression or deficient Epha4 each also reduced pY87-Ephexin level, which is a Rho GEF. Thus, PTP-oc may differentially regulate Rac signaling vs. Rho signaling through dephosphorylation of EphA4, which has shown to have opposing effects on Rac-GTPase vs. Rho-GTPase through differential regulation of Vav3 vs. Ephexin. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Biochemistry 02/2015; 116(8). DOI:10.1002/jcb.25137 · 3.26 Impact Factor
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    • "Considering the biochemical features of a2-chimaerin as a RacGAP, which regulates actin cytoskeleton dynamics, morphological abnormalities in axons or dendritic spines are primary candidates. a2-chimaerin-deficient mice display abnormal axon guidance of the CST and CPG (Beg et al., 2007; Iwasato et al., 2007; Wegmeyer et al., 2007). In humans, gain-of-function mutations of the a-chimaerin gene CHN1 cause Duane's retraction syndrome, an eye movement disorder caused by the disruption of axon guidance in the ocular motor system (Miyake et al., 2008). "
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    ABSTRACT: A major concern in neuroscience is how cognitive ability in adulthood is affected and regulated by developmental mechanisms. The molecular bases of cognitive development are not well understood. We provide evidence for the involvement of the α2 isoform of Rac-specific guanosine triphosphatase (GTPase)-activating protein (RacGAP) α-chimaerin (chimerin) in this process. We generated and analyzed mice with global and conditional knockouts of α-chimaerin and its isoforms (α1-chimaerin and α2-chimaerin) and found that α-chimaerin plays a wide variety of roles in brain function and that the roles of α1-chimaerin and α2-chimaerin are distinct. Deletion of α2-chimaerin, but not α1-chimaerin, beginning during early development results in an increase in contextual fear learning in adult mice, whereas learning is not altered when α2-chimaerin is deleted only in adulthood. Our findings suggest that α2-chimaerin acts during development to establish normal cognitive ability in adulthood.
    Cell Reports 09/2014; 8(5). DOI:10.1016/j.celrep.2014.07.047 · 8.36 Impact Factor
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    • "The collapse or local retraction of neuronal growth cones and dendritic spines (the small protrusions on dendrites bearing excitatory synapses ) are well-known repulsive effects of EphA receptors that depend on Rho family GTPases (Fig. 3B,C) (Wahl et al. 2000; Murai et al. 2003; Fu et al. 2007). Growth cone collapse involves RhoA activation, for example, by the GEF Ephexin1 (Shamah et al. 2001; Sahin et al. 2005), and Rac1 inactivation, for example, by the GAP a2-Chimaerin (Beg et al. 2007; Iwasato et al. 2007; Shi et al. 2007; Wegmeyer et al. 2007). However Rac1 activation, which can occur downstream of Vav family GEFs, is also required for growth cone collapse and to process retraction by enabling endocytic removal of adhesive Eph receptor– ephrin complexes from sites of cell– cell contact (Cowan et al. 2005; Yoo et al. 2011). "
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    ABSTRACT: The Eph receptors are the largest of the RTK families. Like other RTKs, they transduce signals from the cell exterior to the interior through ligand-induced activation of their kinase domain. However, the Eph receptors also have distinctive features. Instead of binding soluble ligands, they generally mediate contact-dependent cell-cell communication by interacting with surface-associated ligands-the ephrins-on neighboring cells. Eph receptor-ephrin complexes emanate bidirectional signals that affect both receptor- and ephrin-expressing cells. Intriguingly, ephrins can also attenuate signaling by Eph receptors coexpressed in the same cell. Additionally, Eph receptors can modulate cell behavior independently of ephrin binding and kinase activity. The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. Its abnormal function has been implicated in various diseases, including cancer. Thus, Eph receptors represent promising therapeutic targets. However, more research is needed to better understand the many aspects of their complex biology that remain mysterious.
    Cold Spring Harbor perspectives in biology 09/2013; 5(9). DOI:10.1101/cshperspect.a009159 · 8.68 Impact Factor
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