Snip1 and PRC2 coordinate intrinsic apoptosis, cell division, and neurogenesis in the developing brain

ABSTRACT Brain development requires the intricate balance between division, death, and differentiation of neural progenitor cells (NPCs). Here, we report the discovery of Snip1 as a key regulator of these NPC phases. The conditional deletion of Snip1 in the mouse embryonic brain causes dysplasia with robust induction of caspase 9-dependent apoptosis. In NPCs, Snip1 suppresses the genetic programs of apoptosis and developmental signaling pathways and promotes the genetic programs of cell cycle, neurogenesis, and cortical development. Mechanistically, Snip1 binds to the Polycomb complex PRC2, co-occupies gene targets with PRC2, and regulates H3K27 marks. Deletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia and partially restore genetic programs and tissue development in the Snip1-depleted brain. Our findings suggest that Snip1 exerts loci-dependent regulation of PRC2 and H3K27me3 to toggle between cell fates in the developing brain.