Le rôle du gène de la polarité apico-basale SCRIBBLE1 dans les anomalies de tube neural
Scribble (Scrib) is a key regulator of apicobasal polarity (ABP) of epithelial cells, presynaptic architecture, and short-term synaptic plasticity in Drosophila. In mammals, its homolog Scrib1 has been implicated in AB polarity and has long been studied as a tumor suppressor gene. However, Scrib1 was also implicated in another form of polarity called planar cell polarity (PCP) where epithelial cells become polarized along the plane of the epithelium. In vertebrates, PCP, also called the non-canonical Frizzled/Dishevelled (Fz/Dvl) pathway, mediates a morphogenetic process called convergent extension (CE) during gastrulation and neural tube formation. 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.
Scribble1 Neural tube defects Planar cell polarity Apicobasal polarity