scholarly journals Vangl2-environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension

2021 ◽  
Author(s):  
Oleksandr Nychyk ◽  
Gabriel L. Galea ◽  
Matteo Molè ◽  
Dawn Savery ◽  
Nicholas D.E. Greene ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Cell Polarity ◽  
Neural Tube ◽  
Planar Cell Polarity ◽  
Gene Mutations ◽  
Positive Control ◽  
Mouse Embryos ◽  
Environment Interaction ◽  
Convergent Extension ◽  
Partial Loss

Planar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD). Some humans with NTDs also have PCP gene mutations but these are heterozygous, not homozygous as in mice. Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs. We found that reduced sulfation of glycosaminoglycans interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause craniorachischisis in cultured mouse embryos, with rescue by exogenous sulphate. We hypothesised this glycosaminoglycan-PCP interaction may regulate CE but, surprisingly, DiO labeling of the embryonic node demonstrates no abnormality of midline axial extension in sulfation-depleted Lp/+ embryos. Positive-control Lp/Lp embryos show severe CE defects. Abnormalities were detected in the size and shape of somites that flank the closing neural tube in sulfation-depleted Lp/+ embryos. We conclude that failure of closure initiation can arise by a mechanism other than faulty neuroepithelial CE, with possible involvement of matrix-mediated somite expansion, adjacent to the closing neural tube.

scholarly journals Severe neural tube defects due to failure of closure initiation can arise without abnormality of neuroepithelial convergent extension

2021 ◽  
Author(s):  
Oleksandr Nychyk ◽  
Gabriel L Galea ◽  
Matteo J Mole ◽  
Dawn Savery ◽  
Nicholas Greene ◽  
...  
Keyword(s):  
Neural Tube ◽  
Planar Cell Polarity ◽  
Gene Mutations ◽  
Initiation Site ◽  
Positive Control ◽  
Severe Form ◽  
Neural Tube Closure ◽  
Null Alleles ◽  
Convergent Extension ◽  
Partial Loss

Planar cell polarity (PCP) signalling is vital for initiation of neural tube closure in mice, with diminished convergent extension (CE) cell movements leading to a severe form of neural tube defect (NTD), termed craniorachischisis (CRN). Some human NTDs are also associated with PCP gene mutations, but affected individuals are generally heterozygous, whereas PCP homozygosity or compound heterozygosity is needed to produce CRN in mice. This suggests human NTDs may involve other genetic or environmental factors, that interact with partial loss of PCP function. We found that reduced sulfation OF glycosaminoglycans (GAGs) interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause CRN in mice. Here, we hypothesised that this GAG-PCP interaction may regulate convergent extension movements, and hence lead to severe NTDs in the context of only partial loss of PCP function. Both Lp and null alleles of Vangl2 gave similar findings. Culture of E8.5 embryos in the presence of chlorate (a GAG sulfation inhibitor), or enzymatic cleavage of GAG chains, led to failure of NT closure initiation in the majority of Lp/+ embryos, whereas few +/+ littermates exhibited CRN. The chlorate effect was rescued by exogenous sulphate. Surprisingly, DiO labeling of the embryonic node demonstrated no abnormality of midline axial extension in chlorate-treated Lp/+ embryos that developed CRN. In contrast, positive control Lp/Lp embryos displayed severe convergent extension defects in this assay. Morphometric analysis of the closure initiation site revealed abnormalities in the size and shape of somites that flank the closing neural tube in chlorate-treated Lp/+ embryos. We conclude that severe NTDs involving failure of closure initiation can arise by a mechanism other than faulty neuroepithelial convergent extension. Matrix-mediated expansion of somites, flanking the closing neural tube, may be required for closure initiation.

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

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.

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

2014 ◽  
Vol 100 (8) ◽  
pp. 633-641 ◽  
Author(s):  
Patrizia De Marco ◽  
Elisa Merello ◽  
Gianluca Piatelli ◽  
Armando Cama ◽  
Zoha Kibar ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Planar Cell Polarity ◽  
Gene Mutations ◽  
Polarity Gene

scholarly journals Coupling Planar Cell Polarity Signaling to Morphogenesis

2002 ◽  
Vol 2 ◽  
pp. 434-454 ◽  
Author(s):  
Jeffrey D. Axelrod ◽  
Helen McNeill
Keyword(s):  
Cell Polarity ◽  
Planar Cell Polarity ◽  
Fruit Fly ◽  
Convergent Extension ◽  
Cytoskeletal Reorganization ◽  
Directional Information ◽  
Cochlear Hair Cell ◽  
Cellular Asymmetry ◽  
Pcp Signaling ◽  
Unknown Signal

Epithelial cells and other groups of cells acquire a polarity orthogonal to their apical–basal axes, referred to as Planar Cell Polarity (PCP). The process by which these cells become polarized requires a signaling pathway using Frizzled as a receptor. Responding cells sense cues from their environment that provide directional information, and they translate this information into cellular asymmetry. Most of what is known about PCP derives from studies in the fruit fly,Drosophila. We review what is known about how cells translate an unknown signal into asymmetric cytoskeletal reorganization. We then discuss how the vertebrate processes of convergent extension and cochlear hair-cell development may relate toDrosophilaPCP signaling.

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