Dorsal-ventral patterning of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminence. While Bone morphogenetic protein (BMP), Wnt, and Sonic hedgehog (Shh) signaling are known to determine regional identity along the dorsoventral axis, how the region-specific expression of these morphogens is established remains unclear. Here we show that the Polycomb group (PcG) protein Ring1 contributes to the ventralization of the mouse telencephalon. Deletion of Ring1b or both Ring1a and Ring1b in neuroepithelial cells induces ectopic expression of dorsal genes, including those for BMP and Wnt ligands, as well as attenuated expression of the gene for Shh, a key morphogen for ventralization, in the ventral telencephalon. We observe PcG protein–mediated trimethylation of histone 3 at lysine-27 and binding of Ring1B at BMP and Wnt ligand genes specifically in the ventral region. Furthermore, forced activation of BMP or Wnt signaling represses Shh expression. Our results thus indicate that PcG proteins suppress BMP and Wnt signaling in a region-specific manner and thereby allow proper Shh expression and development of the ventral telencephalon.

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.

During brain development, neural precursor cells (NPCs) in different brain regions produce different types of neurons, and each of these regions plays a different role in the adult brain. Therefore, precise regionalization is essential in the early stages of brain development, and irregular regionalization has been proposed as the cause of neurodevelopmental disorders. The mechanisms underlying brain regionalization have been well studied in terms of morphogen-induced expression of critical transcription factors for regionalization. NPC potential in different brain regions is defined by chromatin structures that regulate the plasticity of gene expression. Herein, we present recent findings on the importance of chromatin structure in brain regionalization, particularly with respect to its regulation by Polycomb-group proteins and chromatin accessibility.

Recent studies have demonstrated that epigenetic modifications are deeply involved in neurogenesis; however, the precise mechanisms remain largely unknown. To determine the role of UTX (also known as KDM6A), a demethylase of histone H3K27, in neural development, we generated Utx-deficient mice in neural stem/progenitor cells (NSPCs). Since Utx is an X chromosome-specific gene, the genotypes are sex-dependent; female mice lose both Utx alleles (Utx Δ/Δ ), and male mice lose one Utx allele yet retain one Uty allele, the counterpart of Utx on the Y chromosome (Utx Δ/Uty ). We found that Utx Δ/Δ mice exhibited fetal ventriculomegaly and died soon after birth. Immunofluorescence staining and EdU labeling revealed a significant increase in NSPCs and a significant decrease in intermediate-progenitor and differentiated neural cells. Molecular analyses revealed the downregulation of pathways related to DNA replication and increased H3K27me3 levels around the transcription start sites in Utx Δ/Δ NSPCs. These results indicate that UTX globally regulates the expression of genes required for proper neural development in NSPCs, and UTX deficiency leads to impaired cell