DEVELOPMENTAL PROGRESSION FROM EARLY INDIRECT TO LATE DIRECT NEUROGENESIS IS KEY TO CEREBRAL CORTEX ARCHITECTURE

The cerebral cortex must contain the appropriate numbers of neurons in each layer to acquire its proper functional organization. Accordingly, neurogenesis requires precise regulation along development. Cortical neurons made either directly by Radial Glia Cells (RGCs) that self-consume, or indirectly from RGC via Intermediate Progenitor Cells (IPCs) and largely preserving the RGC pool. According to the standing model of cortical development Direct Neurogenesis predominates at early stages of development, and progressively shifts to Indirect Neurogenesis, which predominates at late stages. However, neurogenesis at early stages should be compatible with RGC amplification and neurogenesis at late stages needs to involve RGC consumption, which seems in conflict with the standing model. Here we studied the modes of neurogenesis along cortical development using multiple approaches, including birthdating, live imaging, MADM clone labelling, single cell transcriptomics and computational simulation. Contrary to the established dogma our data show that Indirect neurogenesis clearly predominates at early developmental stages, gradually shifting to Direct Neurogenesis at late stages. This shift is paralleled with transcriptomic changes, highlighting gene known to regulate the generation of IPCs. These findings challenge the current model of cortical neurogenesis, and prompt a re-evaluation of previous and ongoing work about the genetic and molecular mechanisms regulating this process.