Magi1 is a neural member of the membrane-associated guanylate kinase, or MAGUK, subfamily of PDZ proteins and contains six PDZ domains, a GUK domain, and two WW motifs ( Fig. Here, we reveal a pair of novel interactions between the PDZ-binding motif of delta-catenin and the proteins Magi1 and Pdlim5 and provide mechanistic insight into the processes underlying dendrite development. There is evidence that these roles of delta-catenin in dendrite growth are dependent upon its PDZ-binding motif, as loss of this region prevents the increased dendritic arborization induced by delta-catenin overexpression in neurons ( Arikkath et al., 2008). Overexpression of delta-catenin in NIH/3T3 cells, among other nonneuronal cell lines, induces the formation and branching of dendrite-like processes through the remodeling of actin and microtubules ( Kim et al., 2002 Kim et al., 2008a). In neurons, delta-catenin is required for proper dendrite development, as shRNA-mediated knockdown (KD) of delta-catenin leads to inhibition of both dendrite elongation and branching, while overexpression of delta-catenin results in increased dendritic length and complexity ( Martinez et al., 2003 Arikkath et al., 2008). Perturbations in the normal functioning of delta-catenin have been linked to several neurodevelopmental disorders, such as cri-du-chat syndrome, autism, and schizophrenia ( Medina et al., 2000 Vrijenhoek et al., 2008 Turner et al., 2015). Our findings implicate the neural catenin protein delta-catenin in controlling dendritic development following mGluR5 activation. We investigate mechanistic changes elicited by glutamate signaling, specifically through the receptor mGluR5. Despite the extensive evidence for glutamate and its metabotropic receptor’s roles in dendrite development, surprisingly little is known about the mechanisms downstream of its signaling in dendrites. Further, cultured neurons treated with the type 1 mGluR (mGluR1 and mGluR5) agonist 3,5-dihydroxyphenylglycine (DHPG) exhibit increased dendrite growth during early development ( Cruz-Martín et al., 2012). Both hippocampal and cortical neurons of mice lacking Grm5, the gene that encodes the glutamate receptor mGluR5, develop significantly less complex dendritic arbors than controls in vivo ( Ballester-Rosado et al., 2010 Loerwald et al., 2015). Cultured primary hippocampal neurons treated with glutamate develop significantly more complex dendritic arbors when compared with controls, whereas blocking activity of glutamate receptors results in the formation of less complex dendritic arbors ( Charych et al., 2006 Hamad et al., 2011 Previtera and Firestein, 2015). Namely, the neurotransmitter glutamate has been strongly implicated in the establishment of dendritic morphology ( Portera-Cailliau et al., 2003 Park et al., 2007 Ballester-Rosado et al., 2010). We thus reveal a “phospho-switch” within delta-catenin, subject to a glutamate-mediated signaling pathway, that assists in balancing the branching versus extension of dendrites during neural development.ĭendrite development is largely governed by the modulation of intracellular pathways by extracellular signaling cues ( Dong et al., 2015). Our data suggest that these complexes affect dendrite development by differentially regulating the small-GTPase RhoA and actin-associated protein Cortactin. Whereas the delta:Pdlim5 complex enhances dendrite branching at the expense of elongation, the delta:Magi1 complex instead promotes lengthening. The phosphorylation state of this motif determines delta-catenin’s ability to bind either Pdlim5 or Magi1. In it, glutamate signaling activates mGluR5 receptors to promote Ckd5-mediated phosphorylation of the C-terminal PDZ-binding motif of delta-catenin. Here, we report a new mechanism instructing dendrites to branch versus extend. While several known processes shape the arbor, little is known of those that govern dendrite branching versus extension. ![]() It is thus vital that, during development, the dendritic arbor is adequately formed to enable proper neural circuit formation and function. In neurons, dendrites form the major sites of information receipt and integration.
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