UTX deficiency in neural stem/progenitor cells results in impaired neural development, fetal ventriculomegaly, and postnatal death

Abstract

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