scholarly journals Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1198 ◽  
Author(s):  
Wang ◽  
Marco ◽  
Capra ◽  
Kibar
Keyword(s):  
Cell Polarity ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Planar Cell Polarity ◽  
Neural Tube Closure ◽  
Convergent Extension ◽  
Complex Genetics ◽  
Pcp Signaling ◽  
Canonical Wnt

Neural tube defects (NTDs), including spina bifida and anencephaly, represent the most severe and common malformations of the central nervous system affecting 0.7–3 per 1000 live births. They result from the failure of neural tube closure during the first few weeks of pregnancy. They have a complex etiology that implicate a large number of genetic and environmental factors that remain largely undetermined. Extensive studies in vertebrate models have strongly implicated the non-canonical Wnt/planar cell polarity (PCP) signaling pathway in the pathogenesis of NTDs. The defects in this pathway lead to a defective convergent extension that is a major morphogenetic process essential for neural tube elongation and subsequent closure. A large number of genetic studies in human NTDs have demonstrated an important role of PCP signaling in their etiology. However, the relative contribution of this pathway to this complex etiology awaits a better picture of the complete genetic architecture of these defects. The emergence of new genome technologies and bioinformatics pipelines, complemented with the powerful tool of animal models for variant interpretation as well as significant collaborative efforts, will help to dissect the complex genetics of NTDs. The ultimate goal is to develop better preventive and counseling strategies for families affected by these devastating conditions.

scholarly journals Snx3 is important for mammalian neural tube closure via its role in canonical and non-canonical WNT signaling

Development ◽  
2020 ◽  
Vol 147 (22) ◽  
pp. dev192518 ◽  
Author(s):  
Heather Mary Brown ◽  
Stephen A. Murray ◽  
Hope Northrup ◽  
Kit Sing Au ◽  
Lee A. Niswander
Keyword(s):  
Wnt Signaling ◽  
Neural Tube ◽  
Neural Tube Closure ◽  
Convergent Extension ◽  
Sorting Nexin ◽  
Mutant Mouse Embryos ◽  
Functionally Impaired ◽  
Canonical Wnt

ABSTRACTDisruptions in neural tube (NT) closure result in neural tube defects (NTDs). To understand the molecular processes required for mammalian NT closure, we investigated the role of Snx3, a sorting nexin gene. Snx3−/− mutant mouse embryos display a fully-penetrant cranial NTD. In vivo, we observed decreased canonical WNT target gene expression in the cranial neural epithelium of the Snx3−/− embryos and a defect in convergent extension of the neural epithelium. Snx3−/− cells show decreased WNT secretion, and live cell imaging reveals aberrant recycling of the WNT ligand-binding protein WLS and mis-trafficking to the lysosome for degradation. The importance of SNX3 in WNT signaling regulation is demonstrated by rescue of NT closure in Snx3−/− embryos with a WNT agonist. The potential for SNX3 to function in human neurulation is revealed by a point mutation identified in an NTD-affected individual that results in functionally impaired SNX3 that does not colocalize with WLS and the degradation of WLS in the lysosome. These data indicate that Snx3 is crucial for NT closure via its role in recycling WLS in order to control levels of WNT signaling.

scholarly journals Mutations associated with human neural tube defects display disrupted planar cell polarity in Drosophila

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ashley C Humphries ◽  
Sonali Narang ◽  
Marek Mlodzik
Keyword(s):  
Cell Polarity ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Developmental Disorders ◽  
Planar Cell Polarity ◽  
Causative Factor ◽  
Limited Data ◽  
Post Translational Modification ◽  
Pcp Signaling

Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD patients found to harbor mutations in PCP genes, but there is limited data on whether these mutations disrupt PCP signaling in vivo. The core PCP gene Van Gogh (Vang), Vangl1/2 in mammals, is the most specific for PCP. We thus addressed potential causality of NTD-associated Vangl1/2 mutations, from either mouse or human patients, in Drosophila allowing intricate analysis of the PCP pathway. Introducing the respective mammalian mutations into Drosophila Vang revealed defective phenotypic and functional behaviors, with changes to Vang localization, post-translational modification, and mechanistic function, such as its ability to interact with PCP effectors. Our findings provide mechanistic insight into how different mammalian mutations contribute to developmental disorders and strengthen the link between PCP and NTD. Importantly, analyses of the human mutations revealed that each is a causative factor for the associated NTD.

scholarly journals Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure

Development ◽  
2007 ◽  
Vol 134 (4) ◽  
pp. 789-799 ◽  
Author(s):  
P. Ybot-Gonzalez ◽  
D. Savery ◽  
D. Gerrelli ◽  
M. Signore ◽  
C. E. Mitchell ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Neural Tube ◽  
Planar Cell Polarity ◽  
Neural Tube Closure ◽  
Convergent Extension ◽  
Tube Closure ◽  
Planar Cell Polarity Signalling

Role of the planar cell polarity geneProtein tyrosine kinase 7in neural tube defects in humans

2015 ◽  
Vol 103 (12) ◽  
pp. 1021-1027 ◽  
Author(s):  
Mingqin Wang ◽  
Patrizia De Marco ◽  
Elisa Merello ◽  
Pierre Drapeau ◽  
Valeria Capra ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Polarity ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Planar Cell Polarity

scholarly journals Independent Mutations in MouseVangl2That Cause Neural Tube Defects inLooptailMice Impair Interaction with Members of theDishevelledFamily

2004 ◽  
Vol 279 (50) ◽  
pp. 52703-52713 ◽  
Author(s):  
Elena Torban ◽  
Hui-Jun Wang ◽  
Normand Groulx ◽  
Philippe Gros
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Neural Tube Defect ◽  
Planar Cell Polarity ◽  
Cell Types ◽  
Biochemical Properties ◽  
Model Organisms ◽  
Convergent Extension ◽  
Loss Of Function

Mammalian Vangl1 and Vangl2 are highly conserved membrane proteins that have evolved from a single ancestral proteinStrabismus/Van Goghfound inDrosophila. Mutations in theVangl2gene cause a neural tube defect (craniorachischisis) characteristic of thelooptail(Lp) mouse. Studies in model organisms indicate that Vangl proteins play a key developmental role in establishing planar cell polarity (PCP) and in regulating convergent extension (CE) movements during embryogenesis. The role of Vangl1 in these processes is virtually unknown, and the molecular function of Vangl1 and Vangl2 in PCP and CE is poorly understood. Using a yeast two-hybrid system, glutathioneS-transferase pull-down and co-immunoprecipitation assays, we show that both mouse Vangl1 and Vangl2 physically interact with the three members of the cytoplasmic Dishevelled (Dvl) protein family. This interaction is shown to require both the predicted cytoplasmic C-terminal half of Vangl1/2 and a portion of the Dvl protein containing PDZ and DIX domains. In addition, we show that the two knownVangl2loss-of-function mutations identified in two independentLpalleles associated with neural tube defects impair binding to Dvl1, Dvl2, and Dvl3. These findings suggest a molecular mechanism for the neural tube defect seen inLpmice. Our observations indicate that Vangl1 biochemical properties parallel those of Vangl2 and that Vangl1 might, therefore, participate in PCP and CE either in concert with Vangl2 or independently of Vangl2 in discrete cell types.

scholarly journals Planar Cell Polarity Pathway in Kidney Development and Function

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Brittany Rocque ◽  
Elena Torban
Keyword(s):  
Cell Polarity ◽  
Planar Cell Polarity ◽  
Kidney Development ◽  
Neural Tube Closure ◽  
Convergent Extension ◽  
Oriented Cell Division ◽  
Cell Structures ◽  
Pcp Signaling ◽  
And Function ◽  
Duct Development

The evolutionarily conserved planar cell polarity (PCP) signaling pathway controls tissue polarity within the plane orthogonal to the apical-basal axis. PCP was originally discovered in Drosophila melanogaster where it is required for the establishment of a uniform pattern of cell structures and appendages. In vertebrates, including mammals, the PCP pathway has been adapted to control various morphogenetic processes that are critical for tissue and organ development. These include convergent extension (crucial for neural tube closure and cochlear duct development) and oriented cell division (needed for tubular elongation), ciliary tilting that enables directional fluid flow, and other processes. Recently, strong evidence has emerged to implicate the PCP pathway in vertebrate kidney development. In this review, we will describe the experimental data revealing the role of PCP signaling in nephrogenesis and kidney disease.

scholarly journals Role of Rab11 in planar cell polarity and apical constriction during vertebrate neural tube closure

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Olga Ossipova ◽  
Kyeongmi Kim ◽  
Blue B. Lake ◽  
Keiji Itoh ◽  
Andriani Ioannou ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Neural Tube ◽  
Planar Cell Polarity ◽  
Neural Tube Closure ◽  
Apical Constriction ◽  
Tube Closure
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