Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization

Fares Kharfallah, Marie Claude Guyot, Abdul Rahman El Hassan, Redouane Allache, Elisa Merello, Patrizia De Marco, Graziella Di Cristo, Valeria Capra, Zoha Kibar

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2307-2320
Number of pages14
JournalHuman Molecular Genetics
Volume26
Issue number12
DOIs
Publication statusPublished - Jun 15 2017

Keywords

  • Animals
  • Carrier Proteins
  • Cell Adhesion Molecules
  • Cell Line
  • Cell Polarity
  • Child, Preschool
  • Female
  • Heterozygote
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Mutation
  • Mutation, Missense
  • Neural Tube Defects
  • Journal Article
  • Research Support, Non-U.S. Gov't

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