The planar cell polarity protein VANG-1/Vangl negatively regulates Wnt/β-catenin signaling through a Dvl dependent mechanism

Mentink, Remco A.; Rella, Lorenzo; Radaszkiewicz, Tomasz; Gybeľ, Tomáš; Betist, Marco C.; Bryja, Vı́tězslav; Korswagen, Hendrik C.

doi:10.1371/journal.pgen.1007840

Cited by 32 publications

(27 citation statements)

References 54 publications

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“…3F). Other potentially interesting factors were Vangl1, which modulates Wnt signalling and Trim25, an E3 ubiquitin ligase (Mentink et al, 2018;Munir, 2010) . Interestingly, this analysis only identified a subset of the previously proposed regulators.…”

Section: Identification Of Putative Xist Regulatorsmentioning

confidence: 99%

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Pacini

Dunkel

Mages

et al. 2020

Preprint

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To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI with high temporal resolution in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify Nanog downregulation as its main trigger and discover additional putative Xist regulators. Moreover, we confirm several predictions of the stochastic model of XCI where monoallelic silencing is thought to be ensured through negative feedback regulation. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known Xce effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.

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Section: Identification Of Putative Xist Regulatorsmentioning

confidence: 99%

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Pacini

Dunkel

Mages

et al. 2020

Preprint

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“…Why canonical Wnt-signaling activity has to be downregulated during early phases of neurogenesis remains to be determined. Given the evidence for crosstalk and functional antagonism between different Wnt-pathways (Baksh, Boland et al, 2007, Mentink, Rella et al, 2018, we speculate that sustained -catenin-signaling interferes with noncanonical Wnt-signaling pathways and their essential function in dendrite patterning and growth (Arredondo et al, 2019, Goncalves et al, 2016a, Schafer et al, 2015.…”

Section: Discussionmentioning

confidence: 91%

Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

Heppt

Wittmann

Zhang

et al. 2020

Preprint

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In adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing -catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of -catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

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“…Fig. 5C) and a Vangl2 knock-out cell line (Mentink et al, 2018). With this antibody, we observed that VANGL2 expression was enriched in epithelial cells in both mouse and human embryonic LV ChP (Fig.…”

Section: Embryonic Chp Epithelium Expresses Various Wnt/pcp Componentsmentioning

confidence: 86%

MEIS-WNT5A axis regulates development of 4^thventricle choroid plexus

Kaiser

Jang

Lun

et al. 2020

Preprint

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The choroid plexus (ChP) produces cerebrospinal fluid and forms a critical barrier between the brain and the circulation. While the ChP forms in each brain ventricle, it adopts a different shape in each one and remarkably little is known about the mechanisms underlying its development. Here, we show that epithelial WNT5A is critical for determining fourth ventricle (4V) ChP morphogenesis and size. Systemic Wnt5a knockout, or forced WNT5A overexpression beginning at E10.5, profoundly reduced the size and development of ChP in all ventricles. However, conditional deletion of Wnt5a expression in Foxj1-expressing epithelial cells affected only the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical Wnt signaling via Ror1/Ror2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain-and loss-offunction approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS1 and MEIS2 as upstream regulators of Wnt5a in the 4V ChP epithelium. Children's Hospital) for sharing Wnt5a knockout mice with the Lehtinen lab, and Chen Wu at the BCH Viral Core. We are also thankful to Nikodém Zezula (Masaryk University) for his assistance with the figure graphic design and Mgr. Monika Novákova (Masaryk University) for help with the animal work. We thank MEYS CR for support to the following core facilities: CELLIM of CEITEC supported by the Czech-BioImaging large RI project (LM2018129 funded by MEYS CR), Czech Centre for Phenogenomics (LM2015040), Higher quality and capacity of transgenic model breeding (by MEYS and ERDF, OP RDI CZ.

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The planar cell polarity protein VANG-1/Vangl negatively regulates Wnt/β-catenin signaling through a Dvl dependent mechanism

Cited by 32 publications

References 54 publications

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

MEIS-WNT5A axis regulates development of 4^thventricle choroid plexus

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The planar cell polarity protein VANG-1/Vangl negatively regulates Wnt/β-catenin signaling through a Dvl dependent mechanism

Cited by 32 publications

References 54 publications

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

MEIS-WNT5A axis regulates development of 4thventricle choroid plexus

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MEIS-WNT5A axis regulates development of 4^thventricle choroid plexus