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

AI Article Synopsis

  • Scribble1 (Scrib1) is a key tumor suppressor gene involved in cell polarity, and its mutations in mice lead to severe neural tube defects (NTDs) due to disrupted signaling pathways.
  • Research indicated that while ABP appeared normal in mutant cells, there were abnormalities in the localization of important proteins Par-3 and Vangl2, suggesting Scrib1's role in regulating these proteins.
  • Analysis of NTD patients revealed rare mutations in SCRIB1 that affect protein localization, linking Scrib1's function in preventing NTDs to its interactions with Par-3 and Vangl proteins, rather than directly influencing apicobasal polarity.

Article 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.

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Source
http://dx.doi.org/10.1093/hmg/ddx122DOI Listing

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