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MECP2 expression and role in progenitors of the primate cerebral cortex
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Edité par CCSD -
International audience. MECP2 (methyl-CpG binding protein 2), an X-linked gene encoding the methyl-cytosine binding protein MECP2, is associated with two severe neurological disorders, Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), both characterized by a postnatal onset of symptoms. While the majority of functional studies of MECP2 have focused on late stages of cortical development, the function of MECP2 during embryonic development is still elusive. Here, using immunohistochemistry we have mapped the spatiotemporal expression of MECP2 in the germinal zones of the cerebral cortex in both human and non-human primates (NHP). We report an anteroposterior gradient of MECP2 expression in apical and basal progenitors from the Ventricular Zone and the Outer Sub-Ventricular Zone of the NHP at midcorticogenesis. In order to get a deeper insight in MECP2 expression in the developing primate cortex, we carried out single-cell RNA-Seq profiling (DropSeq protocol as in http://mccarrolllab.com/dropseq/) of over 60 000 cells in the NHP cortex at midcorticogenesis. This allowed to quantify and compare MECP2 expression in progenitors and immature neurons migrating out of the germinal zones. A first independent component analysis (ICA) returned 7 main cell type clusters. Within the neural progenitor cell cluster (NPC), sub-clustering analysis highlights three main subtypes of MECP2 expressing cortical progenitors. In order to explore the early role of MECP2 expression in cortical progenitors, we implemented up and downregulation of its expression in the germinal zones of the primate developing cortex and iPSC derived cerebral organoids. We report consequences on the morphological properties of cortical progenitors, affecting their ability to proliferate and delaminate.
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