DMRTA2 regulates radial glial maintenance and tumorigenicity of pediatric high-grade glioma

DMRTA2 is a member of the evolutionarily conserved transcription factor family involved in various developmental processes including neurogenesis. However, the roles of DMRTA2 in human development and disease are not fully characterized. Single cell RNA-seq data analysis showed that DMRTA2 is robustly expressed in neural progenitors, in particular radial glial (RG) cells, in the human fetal brain. Knockout of DMRTA2 gene in human embryonic stem cell (hESC)-derived cerebral organoids led to smaller organoid size and fewer RG cells. We also found that DMRTA2 is highly and specifically expressed in diffuse hemispheric gliomas, H3G34-mutant (DHG-H3G34), a malignant subtype of pediatric brain tumor. Loss of DMRTA2 resulted in enhanced neuronal differentiation, fewer RG-like glioma cells, and impaired tumorigenicity, suggesting its important role in both normal brain development and the formation of malignant brain tumors.