Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression [astro]

The generation of a correctly-sized cerebral cortex with all-embracing neuronal and glial cell-type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb Repressive Complex 2 (PRC2) and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here we utilize Mosaic Analysis with Double Markers (MADM)-based single cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide mechanisms. In a broader context our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior. Overall design: RNA-Seq of enriched astrocytes from control and sparse deletion of Eed in mouse neocortex using a MADM system