Researchers developed cerebral organoids from human pluripotent stem cells to model human brain development and microcephaly. These 3D organoids recapitulate key features of human brain development, including the organization of progenitor zones and the presence of outer radial glial stem cells. The organoids were used to model microcephaly, a neurodevelopmental disorder characterized by reduced brain size, by using patient-derived induced pluripotent stem cells (iPSCs) and RNA interference (RNAi). The organoids showed premature neuronal differentiation, a defect that could explain the disease phenotype. The study demonstrated that cerebral organoids can recapitulate development and disease of the human brain, providing a valuable tool for studying neurodevelopmental disorders. The organoids were generated using a protocol that focused on improving growth conditions and providing intrinsic cues for development. The organoids displayed various brain regions with distinct identities and were able to model aspects of human brain development, including the formation of cortical layers and the presence of outer radial glial stem cells. The organoids also exhibited functional cerebral cortical neurons with complex branching and axon projections, as well as neural activity. The study highlights the potential of cerebral organoids as a model system for studying human brain development and neurodevelopmental disorders.Researchers developed cerebral organoids from human pluripotent stem cells to model human brain development and microcephaly. These 3D organoids recapitulate key features of human brain development, including the organization of progenitor zones and the presence of outer radial glial stem cells. The organoids were used to model microcephaly, a neurodevelopmental disorder characterized by reduced brain size, by using patient-derived induced pluripotent stem cells (iPSCs) and RNA interference (RNAi). The organoids showed premature neuronal differentiation, a defect that could explain the disease phenotype. The study demonstrated that cerebral organoids can recapitulate development and disease of the human brain, providing a valuable tool for studying neurodevelopmental disorders. The organoids were generated using a protocol that focused on improving growth conditions and providing intrinsic cues for development. The organoids displayed various brain regions with distinct identities and were able to model aspects of human brain development, including the formation of cortical layers and the presence of outer radial glial stem cells. The organoids also exhibited functional cerebral cortical neurons with complex branching and axon projections, as well as neural activity. The study highlights the potential of cerebral organoids as a model system for studying human brain development and neurodevelopmental disorders.