MigPCP · Characterization of the role of Scrib1 and Vangl2 in neuronal migration

Characterization of the role of Scrib1 and Vangl2 in neuronal migration

Publishable summary The general of this project is to elucidate the molecular and cellular mechanisms of the planar cell polarity genes (PCP) Scrib1 and Vangl2 in shaping the mammalian cortex. As planned in the proposal, we have generated so far several conditionnal mice strains in order to determine the impact of the loss of these genes on brain development. Most of the results to date are relative to Scrib1 gene, a potential susceptibility gene in Autism spectrum disorders (ASD) and indicate an involvement of both cell proliferation and migration during cortex development. A scientific manuscript is about to be submitted for peer review for publication in summer 2015 to open access journal as requested by EC policy. Additional research is currently carried out to determine the impact of the Scrib1 partner Vangl2. Results obtained during the last 36 months will undoubtly have a strong impact in the young field of PCP in mammals and neurodevelopment and be able to eventually develop therapeutical approaches for related pathologies. CIG Marie Curie grant has been highly valuable for the fellow researcher, not only to pursue promising researcher in the field of neuroscience but also for his reintegration in the European researcher by obtaining a highly competitive permanent academic research position in Inserm (France). Project objective for the period and main results The general aim of this 3-year project is to elucidate the molecular and cellular mechanisms of the planar cell polarity genes (PCP) Scrib1 and Vangl2 in shaping the mammalian cortex. More specifically, I have analyzed so far the role for Scrib1 in neuronal polarity and migration in vivo. I used conditional knockout mice combined with advance cell imaging analysis to provide powerful approach to address this goal. We believe that experiments from this proposal will bring novel insight into the mechanisms by which PCP genes can regulate neuronal migration and cortex development. In essence, the MigPCP project had 3 major objectives: 1) Establish the pattern of expression of Scrib1 and Vangl2 in the developing cortex 2) To identify a role for Scrib1 and Vangl2 in shaping the mammalian cortex 3) Monitor the impact of Scrib1 and Vangl2 on migration in electroporation-based experiments Work progress and achievements during the period The development of corpus callosum (CC) is necessary for the hemisphere connection; a formation defect can lead to cognitive deficits. In this study, we focused our attention on the Scrib1 gene which is involved in cell polarity and associated with Autism Spectrum disorders. Analysis of Circletail mutants revealed that Scrib1 mutation in the whole embryo generates neural tube defects which prevent any study related to brain development. As an alternative, we used three different cKO strains and overall brain morphogenesis was assessed using several brain conditionnal mouse mutants (cKO) for Scrib1. We concluded that 1) Scrib1 is essential for corpus callosum formation in a non-cell-autonomous manner 2) This CC agenesis is due to a mislocalization of glial cells involved in axonal guidance. 3) Scrib1 controls cortical layer formation during development via neuronal migration process and possibly through proliferation/cell fate. In summary, this study allowed to characterize several function of Scrib1 in cortical morphogenesis, neuronal migration or also midline glial cell localization, likely to impact the CC formation.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз