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
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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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Available from: Alessandro Filosa, Oct 08, 2015
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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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    • "In addition to the vast literature on the PHR proteins, regulation of axon guidance has been documented for the Rac1 inhibitor, chimaerin, which has recently been shown to be ubiquitinated and degraded in a protein kinase C-dependent manner [64]. Both α1- and α2-chimaerin splice forms interact with the EphB1 [65] and EphA4 [65–68] receptors, possibly in a phosphorylation-dependent manner [66, 68], although this detail remains controversial [67]. Association with EphA4 stimulates α2-chimaerin's GTPase activating (GAP) activity, thereby repressing the activity of Rac1 [66–68], while ephrinA1-dependent growth cone collapse is attenuated by α2-chimaerin knockdown [68] or knockout [65, 66]. "
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    ABSTRACT: The ubiquitin-proteasome system (UPS) is most widely known for its role in intracellular protein degradation; however, in the decades since its discovery, ubiquitination has been associated with the regulation of a wide variety of cellular processes. The addition of ubiquitin tags, either as single moieties or as polyubiquitin chains, has been shown not only to mediate degradation by the proteasome and the lysosome, but also to modulate protein function, localization, and endocytosis. The UPS plays a particularly important role in neurons, where local synthesis and degradation work to balance synaptic protein levels at synapses distant from the cell body. In recent years, the UPS has come under increasing scrutiny in neurons, as elements of the UPS have been found to regulate such diverse neuronal functions as synaptic strength, homeostatic plasticity, axon guidance, and neurite outgrowth. Here we focus on recent advances detailing the roles of the UPS in regulating the morphogenesis of axons, dendrites, and dendritic spines, with an emphasis on E3 ubiquitin ligases and their identified regulatory targets.
    Neural Plasticity 02/2013; 2013(3, article e9842):196848. DOI:10.1155/2013/196848 · 3.58 Impact Factor
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