Wnt Regulates Axon Behavior through Changes in Microtubule Growth Directionality: A New Role for Adenomatous Polyposis Coli

Purro, Silvia A.; Ciani, Lorenza; Flight, Monica Hoyos; Stamatakou, Eleanna; Siomou, Eliza; Salinas, Patricia C.

doi:10.1523/jneurosci.2320-08.2008

Cited by 162 publications

(205 citation statements)

References 56 publications

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“…5C). Another downstream target of GSK-3␤ is adenomatous polyposis coli (APC), which promotes microtubule assembly at the growth cone when dephosphorylated (Zhou et al, 2004;Koester et al, 2007;Purro et al, 2008). We found that knockdown of APC also suppressed Dock3-mediated axonal outgrowth after BDNF treatment (Fig.…”

Section: Dock3 Induces Phosphorylation Of Gsk-3␤ At the Plasma Membranementioning

confidence: 81%

“…The importance of CRMPs in axonal formation is highlighted by the evidence that axonal outgrowth is arrested when CRMPs are phosphorylated by some kinases, such as glycogen synthase kinase-3␤ (GSK-3␤), because this phosphorylation causes dissociation of CRMPs from microtubules (Eickholt et al, 2002;Yoshimura et al, 2005). In addition, adenomatous polyposis coli (APC), which promotes microtubule assembly at the growth cone, is another downstream target of GSK-3␤ (Zhou et al, 2004;Koester et al, 2007;Purro et al, 2008), indicating the importance of GSK-3␤ in this dynamic process. In this study, we show that Dock3 binds to GSK-3␤ and inhibits its activity, thereby activating CRMP-2 and APC.…”

Section: Introductionmentioning

confidence: 99%

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Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Namekata

Harada²,

Guo³

et al. 2012

J. Neurosci.

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Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolinhomologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3␤ (GSK-3␤) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3␤ and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3␤ was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly.

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Section: Dock3 Induces Phosphorylation Of Gsk-3␤ At the Plasma Membranementioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Namekata

Harada²,

Guo³

et al. 2012

J. Neurosci.

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“…At the roof plate boundary in the zebrafish diencephalon, a Wntexpressing intermediate target for commissural axons, growth cones normally pause and enlarge before crossing. Wnt can regulate axonal microtubules and induce growth cone enlargement via multiple pathways (Gordon-Weeks, 2004;Ciani and Salinas, 2007;Purro et al, 2008;Salinas and Zou, 2008). We suggest that the additive effects of Wnt signaling at the intermediate target and increased microtubule polymerization and stability in phr mutants cause excessive microtubule looping, preventing growth cones from exiting the paused state.…”

Section: Microtubules and Intermediate Targetsmentioning

confidence: 91%

PHR Regulates Growth Cone Pausing at Intermediate Targets through Microtubule Disassembly

Hendricks

Jesuthasan²

2009

J. Neurosci.

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Axonal growth cones use intermediate targets to navigate in the developing nervous system. Encountering these sites is correlated with growth cone pausing. PHR (Phr1, Esrom, Highwire, RPM-1) is a large neuronal ubiquitin ligase that interacts with multiple signaling pathways. Mouse and zebrafish phr mutants have highly penetrant axon pathfinding defects at intermediate targets. Mouse phr mutants contain excessive microtubules in the growth cone, which has been attributed to upregulation of DLK/p38 signaling. Here, we ask whether this pathway and microtubule misregulation are indeed linked to guidance errors in the vertebrate brain, using the zebrafish. By live imaging, we show that loops form when microtubules retract without depolymerizing. JNK, but not p38, phosphorylation is increased in mutant growth cones. However microtubule looping cannot be suppressed by inhibiting JNK. The phr microtubule defect can be phenocopied by taxol, while microtubule destabilization in vitro using nocodazole prevents loop formation. Acute disruption in vivo with nocodazole suppresses the intermediate target guidance defect. Given that microtubule looping is associated with growth cone pausing, we propose that microtubule disassembly, mediated by PHR, is essential for exiting the paused state at intermediate targets.

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“…It was furthermore demonstrated that the stabilization of microtubules by Dvl-1 is enhanced by GSK3 inhibition [280]. Studies in C. elegans, Drosophila and vertebrates have led to the conclusion that Wnt/ -catenin signaling may regulate the orientation of the mitotic spindle through Dishevelled [281][282][283].…”

Section: Dishevelledmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Wnt Regulates Axon Behavior through Changes in Microtubule Growth Directionality: A New Role for Adenomatous Polyposis Coli

Cited by 162 publications

References 56 publications

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

Dock3 Stimulates Axonal Outgrowth via GSK-3β-Mediated Microtubule Assembly

PHR Regulates Growth Cone Pausing at Intermediate Targets through Microtubule Disassembly

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

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