Principal Investigator (Last, First, Middle): Anton, Eva S. PROJECT SUMMARY Radial progenitors serve as an instructive matrix to coordinate the generation and placement of appropriate number and types of neurons in the developing cerebral cortex. Radial progenitors divide asymmetrically to generate neurogenic intermediate progenitors (IPs) and the symmetric proliferation of IPs serves to rapidly expand cortical neuronal population. The dynamic maintenance of the balance between radial and intermediate progenitors is of fundamental importance to the generation of right number and types of projection neurons at the right time in the cerebral cortex. Once generated, growth and connectivity of cortical neurons enables the formation of basic neuronal circuitry in the cerebral cortex. The balanced diversity of cortical progenitors and the resultant generation, placement, and connectivity of projection neurons thus serve as a blueprint to guide the formation of an appropriately wired cerebral cortex. Disruptions in these essential features of the developing cerebral cortex are at the core of many human neurodevelopmental disorders including microcephaly, macrocephaly, lissencephaly, epilepsy, schizophrenia, and autism spectrum disorders. However, the molecular logic that instructs progenitor balance and projection neuronal connectivity remains an enigma. This proposal aims to remedy this gap in our understanding of cerebral cortical formation. In particular, (1) we will discover how the developmental balance between radial and intermediate progenitors, vital for the production of right number and types of cortical neurons at the right time, is achieved, (2) define hitherto uncharted, primary cilia-mediated mechanisms guiding projection neuronal growth and connectivity, and (3) determine how changes in these developmental processes can cause cortical malformations underlying human neurodevelopmental disorders. We aim to make these goals attainable by using an innovation driven approach that involves combined application of latest advances in progenitor or neuron type specific mouse genetic models, live imaging, lineage tracing, mapping of signaling interactomes, optogenetic and chemogenetic manipulation of primary cilia signaling, single cell genomics, and functional evaluation of human mutations associated with neurodevelopmental disorders. Understanding how progenitors and neurons are assembled, organized, and connected appropriately to facilitate cerebral cortical formation, offers us the opportunity to rethink and redraw the rules of corticogenesis in the service of better diagnostic and therapeutic insights into neurodevelopmental disorders.