Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning

Department of Developmental Biology, Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2009; 12(3):268-76. DOI: 10.1038/nn.2254
Source: PubMed


It has been suggested that ephrin-B proteins have receptor-like roles in the control of axon pathfinding by repulsion, although it is largely unknown how the reverse signals are coupled to downstream intracellular molecules and how they induce cytoskeletal reorganization at the axon terminal. We found that ephrin-B3 (EB3) was able to function as a repulsive guidance receptor and mediate stereotyped pruning of murine hippocampal mossy fiber axons during postnatal development. Targeted intracellular point mutants showed that axon pruning requires tyrosine phosphorylation-dependent reverse signaling and coupling to the SH2/SH3 adaptor protein Grb4 (also known as Nckbeta/Nck2). Furthermore, we found that the second SH3 domain of Grb4 is required and sufficient for axon pruning/retraction by mediating interactions with Dock180 and PAK to bring about guanine nucleotide exchange and signaling downstream of Rac, respectively. Our results reveal a previously unknown pathway that controls axon pruning and elucidate the biochemical mechanism by which ephrin-B reverse signals regulate actin dynamics to bring about the retraction of growth cones.

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Available from: Mark Henkemeyer, Aug 10, 2015
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    • "The highly conserved dedicator of cytokinesis proteins (Dock) family of proteins play a key role in multiple aspects of neuronal development, including both axonal and dendritic differentiation , in addition to involvement in both neuroinflammation and the differentiation of Schwann cells (Watabe-Uchida et al., 2006; Miyamoto et al., 2007; Li et al., 2008; Yamauchi et al., 2008, 2011; Xu and Henkemeyer, 2009; Miyamoto and Yamauchi, 2010; Kim et al., 2011; Shi, 2013; Xiao et al., 2013). Not surprisingly therefore, Dock proteins have been increasingly recognized to be associated with a variety of neurodegenerative and neuropsychiatric disorders (Table 1). "
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    • "A further set of mutants, with apparently correctly formed CA3 pyramidal and DG layers but more subtle perturbed mossy fiber targeting or pruning, are related to several axon guidance or adhesion molecules. For example inactivation of the semaphorin 3 receptors, plexin A3 and neuropilin 2 (Chen et al., 2000; Giger et al., 2000; Bagri et al., 2003), the guidance receptor ephrin B3 (Xu and Henkemeyer, 2009), and the adhesion molecule nectin (Honda et al., 2006), show mossy fibers which target infrapyramidal, as well as suprapyramidal regions, most probably due to abnormal fasciculation, targeting and pruning. Also, mouse mutants for serum response factor (Knöll et al., 2006), and adhesion molecules Chl1 (Montag-Sallaz et al., 2002), Ncam-180 (Seki and Rutishauser, 1998) and cadherin (Bekirov et al., 2008; Williams et al., 2011), have mossy fibers which aberrantly synapse on CA3 somata within the pyramidal cell layer instead of apical dendrites in the suprapyramidal regions. "
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    • "Interestingly, Dock180 is also important for the axon pruning induced by ephrin-B3 reverse signaling and RhoG.11,12 Dock180 couples to ephrin-B3 through interacting with the adaptor protein Grb4/Nck2, and hence mediating ephrin-B3 signaling toward Rac1 activation and pruning of hippocampal mossy fiber axons.11,13 Moreover, the Dock180-ELMO complex participates in RhoG-mediated reduction of axonal complexity.12 "
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    ABSTRACT: The family of dedicator of cytokinesis (Dock), a protein family that belongs to the atypical Rho guanine nucleotide exchange factors (GEFs) for Rac and/or Cdc42 GTPases, plays pivotal roles in various processes of brain development. To date, 11 members of Docks have been identified in the mammalian system. Emerging evidence has suggested that members of the Dock family are associated with several neurodegenerative and neuropsychiatric diseases, including Alzheimer disease and autism spectrum disorders. This review summarizes recent advances on the understanding of the roles of the Dock protein family in normal and diseased processes in the nervous system. Furthermore, interacting proteins and the molecular regulation of Docks are discussed.
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