XB-ART-57271
Cells
2019 Oct 04;810:. doi: 10.3390/cells8101198.
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Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects.
Wang M
,
Marco P
,
Capra V
,
Kibar Z
.
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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.
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Genes referenced: dvl2 fubp1 npb
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Figure 1. Normal and abnormal neural tube formation. (A) Major steps of neural tube formation. The neural plate overlying the notochord elevates to form the neural folds around the midline, bends at the midline (mhp) and dorsolateral sites (dlhp) then fuses at the opposing tips of the neural folds and separates from the overlying epidermis. (B). Initiation sites of neural tube closure 1–3 in a mouse embryo. Defects in closure 1 and 2 lead to craniorachischisis and anencephaly respectively. Defects in closure at the caudal end of site 1 lead to open spina bifida. (C). Lateral and dorsal views of E18.5 embryos showing craniorachischisis (C′) and open spina bifida (C″, indicated by red arrows) as compared to wild type (C). cc, central canal; dlhp, dorsolateral hinge point; ec, ectoderm; ep, epidermis; fb, forebrain; hb, hindbrain; mb, midbrain; mhp, median hinge point; me, mesoderm; nc, notochord; ncp, notochordal plate; nec, neural crest; np, neural plate; npb, neural plate border; pe, presumptive epidermis; sc, spinal cord; so, somites. |
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Figure 2. The non-canonical Wnt/planar cell polarity signaling pathway (PCP). (A) A simplified diagram of the PCP signaling pathway showing its core components, its downstream effectors and two of its mediators Ptk7/Otk and Scribble1/Scrib. Nomenclature for core proteins is indicated in vertebrates and Drosophila (separated by/). Genetic interactions are indicated by double arrows. (B) An example of a PCP-regulated process in the wing blade of Drosophila. Asymmetric localization of PCP protein complexes at the proximal (Vang-Pk) and distal (Fz-Dsh) sides of adjacent cells mediates the distal positioning and orientation of a single trichome in each cell of the wing epithelium. (C) The process of convergent extension. Cells elongate mediolaterally, move and intercalate with neighboring cells resulting in convergence toward the midline and extension along the anteroposterior axis. During this process, PK and VANGL localize anteriorly whereas FZD and DVL localize posteriorly. (D) A simplified diagram showing a widened neural plate because of a defective convergent extension (CE) of midline neuroepithelial cells. The neural folds will be far apart and will fail to fuse leading to a neural tube defect. |
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