A major long-term goal of this proposal is to understand human brain development and the origins of neurodevelopmental diseases. The cerebral cortex is a structure where model systems, such as mouse or rat, may not capture the complexity of architecture and function relevant for understanding human development and disease. This proposal aims to address the gap in our understanding of human cortical development through the study of primary tissue complemented by human stem cell-derived in vitro model systems, using “cerebral organoids”. Understanding human-specific aspects of brain development is not only critically important for understanding the etiology of neurodevelopmental disorders, including autism and schizophrenia and ultimately developing therapies, but will also benefit our understanding of human cortical evolution, the diversity and lineage of neural cell types, and the mechanisms of cortical expansion - it will help define what makes us unique. The developing human brain contains an enlarged proliferative region, the outer subventricular zone (OSVZ) that is not present in rodents. This study will target two recently discovered neural progenitor cell types found in the OSVZ, outer radial glia (oRG) and intermediate progenitor (IP) cells. These cell types are particularly important as they underlie the huge developmental and evolutionary expansion of the human brain. This proposal seeks to illuminate the complexity of human cortical development in terms of the genomic, cellular, and behavioral features of its constituent oRG and IP neural progenitor cells and their progeny through the key stages of neurogenesis. We plan to discover lineage trajectories that define progenitor-progeny relationships and determine the cellular fates of clonal descendants. We will use novel oRG and IPC markers to enrich progenitor cell populations for analysis, explore the intracellular signaling networks that regulate IP cell expansion, investigate the role of distinct neurogenic niches in creating neuronal diversity, and examine neuron to progenitor signaling pathways that may regulate IPC neurogenesis. Additionally, we will explore the role of oRGs and IPCs in lissencephaly and related neurodevelopmental diseases, and pursue an intriguing relationship between oRG cells and invasive glioblastoma. These ambitious goals are attainable due to recent technological advances, including improvements in single cell genomics, bioinformatics, real time imaging of primary tissue samples, and in vitro models of human cortical development. The outcome holds promise to transform our understanding of human brain development in health and disease.