title: Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization.
abstract: Scribble1 (Scrib1) is a tumor suppressor gene that has long been established as an essential component of apicobasal polarity (ABP). In mouse models, mutations in Scrib1 cause a severe form of neural tube defects (NTDs) as a result of a defective planar cell polarity (PCP) signaling. In this study, we dissected the role of Scrib1 in the pathogenesis of NTDs in its mouse mutant Circletail (Crc), in cell lines and in a human NTD cohort. While there were no obvious defects in ABP in the Scrib1Crc/Crc neuroepihelial cells, we identified an abnormal localization of the apical protein Par-3 and of the PCP protein Vangl2. These results were concordant with those obtained following a partial knockdown of Scrib1 in MDCK II cells. Par-3 was able to rescue the localization defect of Vangl1 (paralog of Vangl2) caused by partial knockdown of Scrib1 suggesting that Scrib1 exerts its effect on Vangl1 localization indirectly through Par-3. This conclusion is supported by our findings of an apical enrichment of Vangl1 following a partial knockdown of Par-3. Re-sequencing analysis of SCRIB1 in 473 NTD patients led to the identification of 5 rare heterozygous missense mutations that were predicted to be pathogenic. Two of these mutations, p.Gly263Ser and p.Gln808His, and 2 mouse NTD mutations, p.Ile285Lys and p.Glu814Gly, affected Scrib1 membrane localization and its modulating role of Par-3 and Vangl1 localization. Our study demonstrates an important role of Scrib1 in the pathogenesis of NTDs through its mediating effect of Par-3 and Vangl1/2 localization and most likely independently of ABP.
authors.affiliation: Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, Montréal, QC H3T 1C5, Canada.
authors.forename: Fares
authors.initials: F
authors.lastname: Kharfallah
authors.affiliation: Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, Montréal, QC H3T 1C5, Canada.
authors.forename: Marie Claude
authors.initials: MC
authors.lastname: Guyot
authors.affiliation: Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, Montréal, QC H3T 1C5, Canada.
authors.forename: Abdul Rahman
authors.initials: AR
authors.lastname: El Hassan
authors.affiliation: Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, Montréal, QC H3T 1C5, Canada.
authors.forename: Redouane
authors.initials: R
authors.lastname: Allache
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, Montréal, QC H3T 1C5, Canada.
authors.forename: Graziella
authors.initials: G
authors.lastname: Di Cristo
authors.affiliation: U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.affiliation: Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, Montréal, QC H3T 1C5, Canada.
authors.forename: Zoha
authors.initials: Z
authors.lastname: Kibar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C115084:Pard3 protein, mouse; C528120:Vangl1 protein, mouse; C508433:scrib protein, mouse