Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Marco, Patrizia De; Merello, Elisa; Piatelli, Gianluca; Cama, Armando; Kibar, Zoha; Capra, Valeria

doi:10.1002/bdra.23255

Cited by 43 publications

(36 citation statements)

References 74 publications

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“…The first identified mutations were in Vang-like protein 1 (VANGL1) 116 , but since then, mutations in essentially all the core PCP genes have now been identified in human NTD patients. These individual findings are too numerous to list here but have been comprehensively delineated elsewhere 122,123 . Several studies also provide mechanistic insights, revealing that NTD-associated mutations disrupt known interactions among PCP proteins and/or disrupt their subcellular localization 116,124–126 .…”

Section: Introductionmentioning

confidence: 95%

Planar cell polarity in development and disease

Butler

Wallingford

2017

Nat Rev Mol Cell Biol

469

488

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Planar Cell Polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted Wnt ligands, and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking, and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.

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Section: Introductionmentioning

confidence: 95%

Planar cell polarity in development and disease

Butler

Wallingford

2017

Nat Rev Mol Cell Biol

469

488

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“…Mice with genetic disruptions in critical modulators of Wnt/PCP signaling, including Dact1 (Dapper, Frodo), Scribble (Scrib), cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), Dvl2, Vangl1, and Vangl2, have highly penetrant NTD phenotypes [40,41,42,43,44]. Importantly, human genomic studies of patients with NTDs have also revealed mutations in several of these same Wnt/PCP pathway genes [45,46,47,48,49,50,51,52]. A role for the Wnt/β-catenin pathway is indicated in this process as well.…”

Section: Neural Plate Specification and Neural Tube Formationmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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“…Here, recessive mutations in vangl2 result in severe neural tube defects associated with abnormal morphogenesis of the floor plate neuroectoderm [6, 7]. Humans with mutations in VANGL1 or VANGL2 also develop neural tube closure defects [8]. Accumulating data also suggest a role for VANGL proteins during tumor progression and invasion [9, 10].…”

Section: Introductionmentioning

confidence: 99%

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

Jessen

2017

Experimental Cell Research

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Planar cell polarity (PCP) proteins are implicated in a variety of morphogenetic processes including embryonic cell migration and potentially cancer progression. During zebrafish gastrulation, the transmembrane protein Vang-like 2 (VANGL2) is required for PCP and directed cell migration. These cell behaviors occur in the context of a fibrillar extracellular matrix (ECM). While it is thought that interactions with the ECM regulate cell migration, it is unclear how PCP proteins such as VANGL2 influence these events. Using an in vitro cell culture model system, we previously showed that human VANGL2 negatively regulates membrane type-1 matrix metalloproteinase (MMP14) and activation of secreted matrix metalloproteinase 2 (MMP2). Here, we investigated the functional relationship between VANGL2, integrin αvβ3, and MMP2 activation. We provide evidence that VANGL2 regulates cell surface integrin αvβ3 expression and adhesion to fibronectin, laminin, and vitronectin. Inhibition of MMP14/MMP2 activity suppressed the cell adhesion defect in VANGL2 knockdown cells. Furthermore, our data show that MMP14 and integrin αv are required for increased proteolysis by VANGL2 knockdown cells. Lastly, we have identified integrin αvβ3 as a novel VANGL2 binding partner. Together, these findings begin to dissect the molecular underpinnings of how VANGL2 regulates MMP activity and cell adhesion to the ECM.

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Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Cited by 43 publications

References 74 publications

Planar cell polarity in development and disease

Planar cell polarity in development and disease

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

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