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

Wang, Mingqin; Marco, Patrizia De; Capra, Valeria; Kibar, Zoha

doi:10.3390/cells8101198

Cited by 65 publications

(65 citation statements)

References 111 publications

(192 reference statements)

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“…Authors of a recent review list genes containing deleterious rare variants that have been associated with NTDs in humans. This study proffers ANKRD6, CELSR1, CELSR2, CELSR3, DVL2, DVL3, FZD, PK1, VANGL1, VANGL2, LRP6, PTK7, and SCRIB1 as associated genes [68]. Except for DVL2, our study may appear not to corroborate findings in their review.…”

Section: Perspectivecontrasting

confidence: 89%

Burden of rare deleterious variants in WNT signaling genes among 511 myelomeningocele patients

et al. 2020

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Genes in the noncanonical WNT signaling pathway controlling planar cell polarity have been linked to the neural tube defect myelomeningocele. We hypothesized that some genes in the WNT signaling network have a higher mutational burden in myelomeningocele subjects than in reference subjects in gnomAD. Exome sequencing data from 511 myelomeningocele subjects was obtained in-house and data from 29,940 ethnically matched subjects was provided by version 2 of the publicly available Genome Aggregation Database. To compare mutational burden, we collapsed rare deleterious variants across each of 523 human WNT signaling genes in case and reference populations. Ten WNT signaling genes were disrupted with a higher mutational burden among Mexican American myelomeningocele subjects compared to reference subjects (Fishers exact test, P � 0.05) and seven different genes were disrupted among individuals of European ancestry compared to reference subjects. Gene ontology enrichment analyses indicate that genes disrupted only in the Mexican American population play a role in planar cell polarity whereas genes identified in both populations are important for the regulation of canonical WNT signaling. In summary, evidence for WNT signaling genes that may contribute to myelomeningocele in humans is presented and discussed.

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Section: Perspectivecontrasting

confidence: 89%

Burden of rare deleterious variants in WNT signaling genes among 511 myelomeningocele patients

et al. 2020

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“…Neural tube closure, which occurs during the fourth week of human gestation, is divided into four distinct phases (Wang et al, 2019). First, a subset of medial ectodermal cells is induced to differentiate into neural progenitors, which form the neural plate.…”

Section: Introductionmentioning

confidence: 99%

Functional Validation of CLDN Variants Identified in a Neural Tube Defect Cohort Demonstrates Their Contribution to Neural Tube Defects

et al. 2020

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Neural tube defects (NTDs) are severe malformations of the central nervous system that affect 1-2 individuals per 2,000 births. Their etiology is complex and involves both genetic and environmental factors. Our recent discovery that simultaneous removal of Cldn3,-4, and-8 from tight junctions results in cranial and spinal NTDs in both chick and mouse embryos suggests that claudins play a conserved role in neural tube closure in vertebrates. To determine if claudins were associated with NTDs in humans, we used a Fluidigm next generation sequencing approach to identify genetic variants in CLDN loci in 152 patients with spinal NTDs. We identified eleven rare and four novel missense mutations in ten CLDN genes. In vivo validation of variant pathogenicity using a chick embryo model system revealed that overexpression of four variants caused a significant increase in NTDs: CLDN3 A128T, CLDN8 P216L, CLDN19 I22T, and E209G. Our data implicate rare missense variants in CLDN genes as risk factors for spinal NTDs and suggest a new family of proteins involved in the pathogenesis of these malformations.

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“…Scrib is also known for its involvement in planar cell polarity signaling that ultimately regulates embryonic and postnatal development (Montcouquiol et al, 2003(Montcouquiol et al, , 2006aMoreau et al, 2010;Murdoch et al, 2003). Mutations in SCRIB are described in patients with spina bifida (Lei et al, 2013;Robinson et al, 2012;Wang et al, 2019), one of the most common forms of neural tube defect, found at high frequency in patients of Autism Spectrum disorder (ASD) (Dawson et al, 2009;Lauritsen et al, 2002;Timonen-Soivio et al, 2015). Indeed, accumulating evidence suggests a role of SCRIB, together with other polarity genes, in neurodevelopmental and autistic disorders (for review, see (Sans et al, 2016)).…”

Section: Introductionmentioning

confidence: 99%

Scribble controls social behaviors through the regulation of the ERK/Mnk1 pathway

Moreau

Pietropaolo

Ezan

et al. 2020

Preprint

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Social behavior is a basic domain affected in several neurodevelopmental disorders. Indeed, deficits in social interest, interactions and recognition represent core symptoms of Autism Spectrum Disorder but are also found associated with a heterogeneous set of neuropsychiatric and rare disorders. The SCRIB gene that codes for the polarity protein SCRIBBLE has been identified as a risk gene for spina bifida, the most common type of open neural tube defect, found at high frequencies in autistic patients, as other congenital anomalies, while the deletions/mutations of the 8q24.3 region encompassing SCRIB genes is associated with multisyndromic and rare disorders. Nonetheless, the potential link between SCRIB and ASD-relevant social phenotypes has not been investigated yet. Hence, we performed an extensive behavioral characterization of the circletail line that carries a mutated version of Scrib. Scribcrc/+ mice displayed reduced social interest, lack of preference for social novelty and social reward, and reduced social habituation while other behavioral domains were unaltered. Social deficits were associated with reduced hippocampal volume, upregulation of ERK phosphorylation in specific hippocampal regions, together with increased c-Fos activity in the same brain areas. Importantly, the social alterations were rescued by both direct and indirect pERK inhibition. These results support a specific link between polarity genes, social behaviors and hippocampal functionality, thus suggesting a role for SCRIB in the etiopathology of neurodevelopmental disorders. Furthermore, our data demonstrate the crucial role of the MAPK/ERK signaling pathway, in underlying the social deficits induced by SCRIB mutation, thus supporting its relevance as a therapeutic target.

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

Cited by 65 publications

References 111 publications

Burden of rare deleterious variants in WNT signaling genes among 511 myelomeningocele patients

Burden of rare deleterious variants in WNT signaling genes among 511 myelomeningocele patients

Functional Validation of CLDN Variants Identified in a Neural Tube Defect Cohort Demonstrates Their Contribution to Neural Tube Defects

Scribble controls social behaviors through the regulation of the ERK/Mnk1 pathway

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