Post-transcriptional regulation maintains neurogenic potential of human neural progenitor cells

Increasing evidence supports important roles of post-transcriptional regulation in brain development; however, the precise mechanism remains unclear. Here, we show that Fragile X autosomal homolog 1 (FXR1), a brain-enriched RNA-binding protein (RBP), is essential for human neurogenesis. FXR1-deficient human cortical neural progenitor cells (NPCs) have reduced proliferation and impaired cell cycle exit during differentiation, leading to impaired neuronal differentiation. Transcriptomic and co-expression network analyses revealed FXR1 as an orchestrator of stage-specific gene programs driving neural differentiation. High-mobility group protein B2 (HMGB2), a master transcriptional regulator in stem cells, is a direct target of FXR1. FXR1 and HuR co-regulate HMGB2 mRNA, and their opposing actions on mRNA stability maintain the levels of HMGB2 in human NPCs. Reducing HMGB2 levels in FXR1-deficient NPCs rescues NPC proliferation and neuronal differentiation. Together, these findings establish post-transcriptional regulation as a key mechanism that maintains neurogenic potency of human NPCs.