Vangl2 Promotes Wnt/Planar Cell Polarity-like Signaling by Antagonizing Dvl1-Mediated Feedback Inhibition in Growth Cone Guidance

Shafer, Beth; Onishi, Keisuke; Lo, Charles G.; Çolakoğlu, Gülsen; Zou, Yimin

doi:10.1016/j.devcel.2011.01.002

Cited by 188 publications

(259 citation statements)

References 41 publications

(71 reference statements)

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“…Knocking down Celsr2 expression reduces the length of apical dendrites and the numbers of basal Celsr3 mutant mice have defects in several major axonal tracts, a phenotype similar to that of Fzd3 mutant mice [38,39] . In both mutants, commissural spinal cord axons fail to turn rostrally after crossing the midline [40][41][42] ; thalamocortical, corticofugal and subcerebral axons are unable to traverse the ventral telencephalon to reach their targets, and the development of some commissures is defective.…”

Section: Two Mouse Mutants Of Celsr1 Have Been Identified Inmentioning

confidence: 99%

Planar cell polarity genes, Celsr1-3, in neural development

2012

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flamingo is among the 'core' planar cell-polarity genes, protein of which belongs to a unique cadherin subfamily.In contrast to the classic cadherins, composed of several extracellular cadherin repeats, one transmembrane domain and one cytoplasmic segment linked to catenin binding, Drosophila Flamingo has seven transmembrane segments and a cytoplasmic tail with no catenin-binding sequence. In Drosophila, Flamingo has pleotropic roles in controlling epithelial polarity and neuronal morphogenesis. Three mammalian orthologs of flamingo, Celsr1-3, are widely expressed in the nervous system. Recent work has shown that Celsr1-3 play important roles in neural development, such as in axon guidance, neuronal migration, and cilium polarity. Celsr1-3 single-gene knockout mice exhibit different phenotypes, but there are cooperative interactions among these genes.

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Section: Two Mouse Mutants Of Celsr1 Have Been Identified Inmentioning

confidence: 99%

Planar cell polarity genes, Celsr1-3, in neural development

2012

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“…1A), which is commonly involved in PDZ binding (Hering and Sheng 2002) and may serve as an accessory site to augment FZD clustering by perhaps PDZ proteins. Phosphorylation of the FZD carboxyl region has been observed and is associated with down-regulation of FZD/PCP signaling, such as Fz/Dfz1 phosphorylation by aPKC around the DVL-interacting SxKTxxSW motif in Drosophila (Djiane et al 2005), and Dvl-dependent FZD3 phosphorylation, which inhibits FZD3 endocytosis and signaling, in axon guidance (Shafer et al 2011) and possibly in neural crest induction (Yanfeng et al 2006). However, it is unknown whether phosphorylation regulates FZD function in b-catenin signaling.…”

Section: Fzd and Dvl Interactionmentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

508

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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“…One particularly intriguing aspect of this control is the relationship between Fzd and Dsh. Normally Dsh is thought to act as a downstream effector of Fzd (20)(21)(22), but Dsh can also promote the phosphorylation of Fzd, which attenuates Fzd activity and inhibits downstream PCP signaling (23)(24)(25). The physiological significance of this inhibition is unclear, but it suggests that Dsh proteins both promote and inhibit Wnt signaling in the same cellular context.…”

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confidence: 99%

Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans

Zheng

Diaz‐Cuadros

Chalfie

2015

Proc. Natl. Acad. Sci. U.S.A.

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Wnt proteins regulate axonal outgrowth along the anterior-posterior axis, but the intracellular mechanisms that modulate the strength of Wnt signaling in axon guidance are largely unknown. Using the Caenorhabditis elegans mechanosensory PLM neurons, we found that posteriorly enriched LIN-44/Wnt acts as a repellent to promote anteriorly directed neurite outgrowth through the LIN-17/Frizzled receptor, instead of controlling neuronal polarity as previously thought. Dishevelled (Dsh) proteins DSH-1 and MIG-5 redundantly mediate the repulsive activity of the Wnt signals to induce anterior outgrowth, whereas DSH-1 also provides feedback inhibition to attenuate the signaling to allow posterior outgrowth against the Wnt gradient. This inhibitory function of DSH-1, which requires its dishevelled, Egl-10, and pleckstrin (DEP) domain, acts by promoting LIN-17 phosphorylation and is antagonized by planar cell polarity signaling components Van Gogh (VANG-1) and Prickle (PRKL-1). Our results suggest that Dsh proteins both respond to Wnt signals to shape neuronal projections and moderate its activity to fine-tune neuronal morphology. Wnt signals evoke downstream activity mainly through three different intracellular pathways: the β-catenin-dependent canonical pathway, the planar cell polarity (PCP) pathway, and the Wnt/calcium pathway (13,14). Although the canonical pathway (7, 15) and the Wnt/calcium pathway (16) regulate axon guidance in a few instances, Wnt-mediated axon pathfinding mainly uses the PCP pathway, which activates the small GTPases Rho, Rac, and Cdc42, which regulate cytoskeletal dynamics (17, 18). Studies from mice, Drosophila, and Caenorhabditis elegans collectively suggest that the core components of PCP signaling involved in axon guidance are the Wnt receptor Fzd, the phosphoprotein Dishevelled (Dsh, Dvl), the transmembrane protein Van Gogh/ Strabismus (Vang/Stbm, Vangl) and its adaptor Prickle (Prkl, Pk), and the atypical cadherin Flamingo/starry night (Fmi/Stan, Celsrs), although the requirement for each component may depend on the specific neuron type (17,19).An important question is how these components interact with each other to spatially and temporally control the neuronal response to the Wnt signal. One particularly intriguing aspect of this control is the relationship between Fzd and Dsh. Normally Dsh is thought to act as a downstream effector of Fzd (20-22), but Dsh can also promote the phosphorylation of Fzd, which attenuates Fzd activity and inhibits downstream PCP signaling (23-25). The physiological significance of this inhibition is unclear, but it suggests that Dsh proteins both promote and inhibit Wnt signaling in the same cellular context.Here, using the morphologically well-defined PLM neurons in C. elegans, we find that two Dsh proteins, DSH-1 and MIG-5, act redundantly downstream of Fzd receptor to mediate the repelling activity of Wnt signal, which guides the outgrowth of a long, anteriorly directed neurite away from the cue. At the same time, DSH-1 also provides feedback inhibition to ...

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Vangl2 Promotes Wnt/Planar Cell Polarity-like Signaling by Antagonizing Dvl1-Mediated Feedback Inhibition in Growth Cone Guidance

Cited by 188 publications

References 41 publications

Planar cell polarity genes, Celsr1-3, in neural development

Planar cell polarity genes, Celsr1-3, in neural development

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

Dishevelled attenuates the repelling activity of Wnt signaling during neurite outgrowth in Caenorhabditis elegans

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