Search

Summary The regulation of the proliferation and polarity of neural progenitors is crucial for the development of the brain cortex. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remains to be elucidated. We harnessed human cortical brain organoids to probe the longitudinal impact of GSK3 inhibition through multiple developmental stages. Chronic GSK3 inhibition increased the proliferation of neural progenitors and caused massive derangement of cortical tissue architecture. Single-cell transcriptome profiling revealed a direct impact on early neurogenesis and uncovered a selective role of GSK3 in the regulation of glutamatergic lineages and outer radial glia output. Our dissection of the GSK3-dependent transcriptional network in human corticogenesis underscores the robustness of the programs determining neuronal identity independent of tissue architecture., Graphical Abstract, Highlights • Cortical organoids recapitulate stereotypical neurogenic trajectories • GSK3 inhibition disrupts neuroepithelium polarity and cortical tissue organization • GSK3 activity controls oRG production and neurogenesis, In this article, Testa and colleagues show that the chronic inhibition of GSK3 in human cortical organoids causes early disruption of neural progenitor proliferation and polarity, which turns at later stages into a pronounced defect in neurogenesis and outer radial glia production.