<i>VANGL2</i>Mutations in Human Cranial Neural-Tube Defects

Lei, Yunping; Zhang, Ting; Li, Hong; Wu, Bai Lin; Jin, Li; Wang, Hong Yan

doi:10.1056/nejmc0910820

Cited by 174 publications

(180 citation statements)

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“…In these experiments we focused first on the Xenopus homolog of Drosophila Van Gogh, Vangl2, because it plays pivotal roles in invertebrate and vertebrate planar polarized epithelia (reviewed in Vladar et al, 2009;Wansleeben and Meijlink, 2011), is expressed as a localized mRNA in Xenopus oocytes (see Fig. S2C in the supplementary material) and is the only PCP core component for which a mutation has been identified in human familial and sporadic cases of neural tube defects (Kibar et al, 2009;Kibar et al, 2011;Lei et al, 2011). We first examined the distribution of Vangl2 protein (Goto and Keller, 2002) in oocytes, by immunostaining with a Vangl2 specific antibody.…”

Section: Vangl2 Interacts With the Post-golgi Vesicle Protein Vamp1 Imentioning

confidence: 99%

The roles of maternal Vangl2 and aPKC inXenopusoocyte and embryo patterning

et al. 2011

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SUMMARYThe Xenopus oocyte contains components of both the planar cell polarity and apical-basal polarity pathways, but their roles are not known. Here, we examine the distribution, interactions and functions of the maternal planar cell polarity core protein Vangl2 and the apical-basal complex component aPKC. We show that Vangl2 is distributed in animally enriched islands in the subcortical cytoplasm in full-grown oocytes, where it interacts with a post-Golgi v-SNARE protein, VAMP1, and acetylated microtubules. We find that Vangl2 is required for the stability of VAMP1 as well as for the maintenance of the stable microtubule architecture of the oocyte. We show that Vangl2 interacts with atypical PKC, and that both the acetylated microtubule cytoskeleton and the Vangl2-VAMP1 distribution are dependent on the presence of aPKC. We also demonstrate that aPKC and Vangl2 are required for the cell membrane asymmetry that is established during oocyte maturation, and for the asymmetrical distribution of maternal transcripts for the germ layer and dorsal/ventral determinants VegT and Wnt11. This study demonstrates the interaction and interdependence of Vangl2, VAMP1, aPKC and the stable microtubule cytoskeleton in the oocyte, shows that maternal Vangl2 and aPKC are required for specific oocyte asymmetries and vertebrate embryonic patterning, and points to the usefulness of the oocyte as a model to study the polarity problem.

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Section: Vangl2 Interacts With the Post-golgi Vesicle Protein Vamp1 Imentioning

confidence: 99%

The roles of maternal Vangl2 and aPKC inXenopusoocyte and embryo patterning

et al. 2011

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“…Indeed, missense mutations in VANGL2 and its homolog VANGL1 have been identified in patients with spinal bifida (Kibar et al 2007(Kibar et al , 2009(Kibar et al , 2011 and miscarried fetuses with cranial NT defects such as anencephaly (Lei et al 2010). These studies showed conclusively that disruption of PCP signaling is an important causative factor of NTDs in humans.…”

Section: Neural Tube (Nt) Closurementioning

confidence: 59%

Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

Wang¹,

Sinha²,

Wynshaw‐Boris³

2012

Cold Spring Harbor Perspectives in Biology

106

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“…21 in the N-terminus of this protein causes a loss of function in vivo. 14 In addition, the N-terminal segment of VANGL1/VANGL2 proteins harbors pathological variants (S83L and S84F) associated with sporadic cases of NTD 15,16 ; in particular, S84F maps to a Ser/Thr cluster that is phosphorylated in response to a Wnt5 signaling gradient required for PCP. 17 Hence, the amino terminal segment of Vangl proteins does not harbor critical determinants for PM targeting, but is nevertheless required for other functional aspects.…”

Section: Discussionmentioning

confidence: 99%

“…These include interaction with the PDZ and DIX domains of Dvl1, Dvl2, and Dvl3, which is abrogated by Lp mutations (D255E, S464N) and by NTD specific human variants (R353C, F437S). 6,15 Additionally, the Vangl2 PDZ binding motif recruits the PDZ domain of Scribble, and is disrupted by the Lp variant S464N and by Figure 3. MDCK cells stably transfected with either GFP-tagged hVANGL1 WT or GFP-tagged hVANGL1 amino or carboxy terminal truncated constructs (green) were immunostained with the ER marker calreticulin (red) to determine subcellular localization.…”

Section: Discussionmentioning

confidence: 99%

The intracellular carboxyl terminal domain of Vangl proteins contains plasma membrane targeting signals

Iliescu

Gros

2014

Protein Science

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Vangl1 and Vangl2 are integral membrane proteins that play a critical role in establishing planar cell polarity (PCP) in epithelial cells and are required for convergent extension (CE) movements during embryogenesis. Their proper targeting to the plasma membrane (PM) is required for function. We created discrete deletions at the amino and carboxy termini of Vangl1 and monitored the effect of the mutations on PM targeting in Madin-Darby canine kidney cells. Our results show that the Vangl1 amino terminus lacks PM targeting determinants, and these are restricted to the carboxy terminus, including the predicted PDZBM motif at the C-terminus.

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VANGL2Mutations in Human Cranial Neural-Tube Defects

Cited by 174 publications

References 5 publications

The roles of maternal Vangl2 and aPKC inXenopusoocyte and embryo patterning

The roles of maternal Vangl2 and aPKC inXenopusoocyte and embryo patterning

Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

The intracellular carboxyl terminal domain of Vangl proteins contains plasma membrane targeting signals

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