Staufen2 modulates the temporal dynamics of human neurogenesis in vitro

RNA-binding proteins (RBPs) play a central role in post-transcriptional regulation during brain development, yet their specific functions in coordinating human neural lineage decisions remain poorly understood. Here, we investigate for the first time the role of the double-stranded RBP Staufen2 (STAU2) in human neurogenesis. Characterization of STAU2 knockout iPSC derived cells using scRNA-seq shows that loss of STAU2 disrupts neuroepithelial cell identity and accelerates neural differentiation by altering the activity of key transcription factors and driving early metabolic transitions. Additionally, STAU2 regulates the expression of miRNA host genes and alters miRNA-mediated post- transcriptional control in progenitor cells, which exerts additional effects on STAU2 regulated gene regulatory networks. These changes result in neural progenitor exhaustion, unstructured neural rosettes, and reduced organoid size. Together, our work uncovers a previously unrecognized role for STAU2 as a central regulator of early human neurogenesis, acting through both miRNA-mediated and transcriptional pathways to coordinate progenitor maintenance and neuronal fate specification.