The Wnt/Planar Cell Polarity Pathway Component Vangl2 Induces Synapse Formation through Direct Control of N-Cadherin

Nagaoka, Tadahiro; Ohashi, Riuko; Inutsuka, Ayumu; Sakai, Seiko; Fujisawa, Naoki; Yokoyama, Minesuke; Huang, Yina H.; Igarashi, Michihiro; Kishi, Masashi

doi:10.1016/j.celrep.2014.01.044

Cited by 72 publications

(95 citation statements)

References 53 publications

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“…Germline Vangl2 mutations, either complete loss-of-function or gain-of-function (looptail), lead to massive axon projection defects (as well as other earlier developmental defects, such as an open neural tube), which will secondarily cause synapse formation defects (14,41,42). In two earlier studies, these germline Vangl2 mutants show a decrease in dendritic complexity and spine density (7,11). To identify the biological function of Vangl2 in synapse formation, which occurs postnatally, we crossed a Vangl2 cKO allele (43) with the SLICK-A Cre line to delete Vangl2 postnatally.…”

Section: J)mentioning

confidence: 99%

“…The conserved core planar cell polarity (PCP) components, Frizzled, Dishevelled, Diego, Prickle, Vang(l), and Flamingo (Fmi)/Celsr, form asymmetric complexes at the cadherin-mediated adherens junctions that connect neighboring epithelial cells (3,4). Recent studies suggest that mutations of some components of the PCP signaling pathway, Celsr3/Fmi and Vangl2, affect GABAergic circuit development in zebrafish retina, GABAergic motoneuron synapse development in Caenorhabditis elegans, and hippocampal/cortical glutamatergic and GABAergic synapse formation (5)(6)(7)(8)(9)(10)(11). PCP components are critical regulators of neuronal migration and axon guidance, which take place before synapse formation and their mutations may secondarily affect synapse formation (8)(9)(10)(12)(13)(14)(15)(16)(17)(18)(19).…”

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confidence: 99%

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Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

Thakar

Wang

et al. 2017

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

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The signaling mechanisms that choreograph the assembly of the highly asymmetric pre-and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.Celsr3 | Vangl2 | glutamatergic | synapse formation G lutamatergic synapses, the predominant excitatory synapses in the brain, are asymmetric cell-cell junctions formed from distinct pre-and postsynaptic components involving highly organized complexes of hundreds of proteins across the 20-nm synaptic cleft (1, 2). The signaling pathway that directly assembles these asymmetric protein complexes has not been well understood. Understanding mechanisms of glutamatergic synapse formation will provide important insights into the function and plasticity as well as dysfunction of glutamatergic synapses, which underlie numerous nervous system disorders.Many epithelial tissues show planar cell polarity, the global asymmetry of cellular and tissue morphology and/or structure along the tissue plane (3, 4). The conserved core planar cell polarity (PCP) components, Frizzled, Dishevelled, Diego, Prickle, Vang(l), and Flamingo (Fmi)/Celsr, form asymmetric complexes at the cadherin-mediated adherens junctions that connect neighboring epithelial cells (3, 4). Recent studies suggest that mutations of some components of the PCP signaling pathway, Celsr3/Fmi and Vangl2, affect GABAergic circuit development in zebrafish retina, GABAergic motoneuron synapse development in Caenorhabditis elegans, and hippocampal/cortical glutamatergic and GABAergic synapse formation (5-11). PCP components are critical regulators of neuronal migration and axon guidance, which take p...

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Section: J)mentioning

confidence: 99%

mentioning

confidence: 99%

Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

Thakar

Wang

et al. 2017

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

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“…36,37 Likewise, in mouse hippocampal neurons, Vangl2 controls internalization of adhesion molecule N-cadherin in the postsynaptic dendritic spines, affecting synaptogenesis. 38 We, therefore, suggest that loss of Vangl2 causes suboptimal slit diaphragm remodeling, leading to a delayed podocyte differentiation and glomerular maturation in Vangl2…”

Section: Pcp Pathway and Glomerular Developmentmentioning

confidence: 99%

Deficiency of the Planar Cell Polarity Protein Vangl2 in Podocytes Affects Glomerular Morphogenesis and Increases Susceptibility to Injury

Rocque

Babayeva

et al. 2015

Journal of the American Society of Nephrology

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The planar cell polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Van Gogh-like protein 2 (Vangl2) is central in the PCP pathway; in mice, Vangl2 loss is embryonically lethal because of neural tube defects, and mutations in Vangl2 are associated with human neural tube defects. In the kidney, PCP signaling may be important for tubular morphogenesis and organization of glomerular epithelial cells (podocytes) along the glomerular basement membrane. Podocyte cell protrusions (foot processes) are critical for glomerular permselectivity; loss of foot process architecture results in proteinuria and FSGS. Previously, we showed a profound effect of PCP signaling on podocyte shape, actin rearrangement, cell motility, and nephrin endocytosis. To test our hypothesis that the PCP pathway is involved in glomerular development and function and circumvent lethality of the ubiquitous Vangl2 mutation in the Looptail mouse, we generated a mouse model with a podocyte-specific ablation of the Vangl2 gene. We report here that podocyte-specific deletion of Vangl2 leads to glomerular maturation defects in fetal kidneys. In adult mice, we detected significantly smaller glomeruli, but it did not affect glomerular permselectivity in aging animals. However, in the context of glomerular injury induced by injection of antiglomerular basement membrane antibody, deletion of Vangl2 resulted in exacerbation of injury and accelerated progression to chronic segmental and global glomerular sclerosis. Our results indicate that Vangl2 function in podocytes is important for glomerular development and protects against glomerular injury in adult animals. 26: 576-586, 201526: 576-586, . doi: 10.1681 Renal glomerular visceral epithelial cells (podocytes) are highly polarized cells with complex threedimensional architecture characterized by the presence of unique actin-based projections (foot processes [FPs]). 1 The FPs from neighboring podocytes form intercellular bridges, slit diaphragms, that are the only points of contact between adjacent cells and the base for the permselective filtration barrier, allowing small solutes to pass into the urinary space while retaining large proteins in the blood. 1 Slit diaphragm protein complexes are connected with the podocyte cytoskeleton by various adaptor proteins and serve as a signaling nexus to relay information from the FP surface to control podocyte structure. 2 The characteristic shape of podocytes is directly related to glomerular filtration. Mutations in proteins that link slit diaphragms and the cytoskeleton (e.g., a-actinin-4 and CD2-associated protein) 3,4 or regulators of actin polymerization and organization (e.g., Inverted Formin-2, Myosin 1e, Rho GDP-Dissociation Inhibitor 1, and Cdc42) 5-9 give rise to glomerular dysfunction, such as proteinuria, J Am Soc Nephrol

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“…Vangl2 is expressed in developing motor axons and is essential for axon guidance in the central nervous system (Avilés and Stoeckli, 2016;Ezan and Montcouquiol, 2013;Nagaoka et al, 2014;Shafer et al, 2011;Tissir and Goffinet, 2013). Moreover, Vangl2 was previously shown to be a postsynaptic protein crucial for synaptogenesis in hippocampal cultures (Nagaoka et al, 2014(Nagaoka et al, , 2015. First, we analyzed the pattern of Vangl2 expression during NMJ formation.…”

Section: Loss Of Wnt Function Impairs Nmj Formationmentioning

confidence: 99%

Wnts contribute to neuromuscular junction formation through distinct signaling pathways

et al. 2017

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Understanding the developmental steps that shape formation of the neuromuscular junction (NMJ) connecting motoneurons to skeletal muscle fibers is crucial. Wnt morphogens are key players in the formation of this specialized peripheral synapse, but their individual and collaborative functions and downstream pathways remain poorly understood at the NMJ. Here, we demonstrate through Wnt4 and Wnt11 gain-of-function studies in cell culture or in mice that Wnts enhance acetylcholine receptor (AChR) clustering and motor axon outgrowth. By contrast, loss of Wnt11 or Wnt-dependent signaling in vivo decreases AChR clustering and motor nerve terminal branching. Both Wnt4 and Wnt11 stimulate AChR mRNA levels and AChR clustering downstream of activation of the β-catenin pathway. Strikingly, Wnt4 and Wnt11 co-immunoprecipitate with Vangl2, a core component of the planar cell polarity (PCP) pathway, which accumulates at embryonic NMJs. Moreover, mice bearing a Vangl2 loss-of-function mutation (loop-tail) exhibit fewer AChR clusters and overgrowth of motor axons bypassing AChR clusters. Together, our results provide genetic and biochemical evidence that Wnt4 and Wnt11 cooperatively contribute to mammalian NMJ formation through activation of both the canonical and Vangl2-dependent core PCP pathways.

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The Wnt/Planar Cell Polarity Pathway Component Vangl2 Induces Synapse Formation through Direct Control of N-Cadherin

Cited by 72 publications

References 53 publications

Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation

Deficiency of the Planar Cell Polarity Protein Vangl2 in Podocytes Affects Glomerular Morphogenesis and Increases Susceptibility to Injury

Wnts contribute to neuromuscular junction formation through distinct signaling pathways

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