The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon

Abstract

SummaryPatterning of the dorsal-ventral (D-V) axis of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminences. Morphogenetic signaling by bone morphogenetic protein (BMP), Wnt, Sonic hedgehog (Shh), and fibroblast growth factor (FGF) pathways determines regional identity along this axis. It has remained unclear, however, how region-specific expression patterns of these morphogens along the D-V axis are established, especially at the level of epigenetic (chromatin) regulation. Here we show that epigenetic regulation by Ring1, an essential Polycomb group (PcG) protein, plays a key role in formation of ventral identity in the mouse telencephalon. Deletion of the Ring1b or both Ring1a and Ring1b genes in neuroepithelial cells of the mouse embryo attenuated expression of the gene for Shh, a key morphogen for induction of ventral identity, and induced misexpression of dorsal marker genes including those for BMP and Wnt ligands in the ventral telencephalon. PcG protein–mediated trimethylation of histone H3 on lysine-27 (H3K27me3) was also apparent at BMP and Wnt ligand genes in wild-type embryos. Importantly, forced activation of Wnt or BMP signaling repressed the expression of Shh in organotypic and dissociated cultures of the early-stage telencephalon. Our results thus indicate that epigenetic regulation by PcG proteins—and, in particular, that by Ring1— confers a permissive state for the induction of Shh expression through suppression of BMP and Wnt signaling pathways, which in turn allows the development of ventral identity in the telencephalon.

New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

“…Extending Neurog1 gene expression and derepressing the expression of neuronal lineage genes, Ring1B and Ezh2 deletions also delayed the onset of gliogenesis, indicating that PRC1 and PRC2 control the neurogenic-to-gliogenic fate switch in cortical NPCs ( Hirabayashi et al, 2009 ). Recently, Ring1b was also shown to control the spatial expression pattern of Neurog1 , with Ring1b deletion expanding Neurog1 expression further ventrally to overlap with Ascl1 expression in the murine E10 telencephalon ( Eto et al, 2020 ). Surprisingly, while Neurog1/2 have been shown to repress Ascl1 expression in the cortex, establishing mutually exclusive expression patterns, Ring1b deletion markedly increased Neurog1/Ascl1 double + NPCs, suggesting that PcG proteins may also regulate mutual exclusivity of proneural TF expression ( Eto et al, 2020 ).…”

“…Recently, Ring1b was also shown to control the spatial expression pattern of Neurog1 , with Ring1b deletion expanding Neurog1 expression further ventrally to overlap with Ascl1 expression in the murine E10 telencephalon ( Eto et al, 2020 ). Surprisingly, while Neurog1/2 have been shown to repress Ascl1 expression in the cortex, establishing mutually exclusive expression patterns, Ring1b deletion markedly increased Neurog1/Ascl1 double + NPCs, suggesting that PcG proteins may also regulate mutual exclusivity of proneural TF expression ( Eto et al, 2020 ). Ring1b has also been shown to temporally limit the production of subcerebral neurons by NPCs through repression of Fezf2 expression ( Morimoto-Suzki et al, 2014 ), which is a known transcriptional target of Neurog2.…”