CONSERVATION AND DIVERGENCE OF GENETIC MECHANISMS REGULATING CEREBRAL CORTEX NEUROGENESIS IN EVOLUTION

In the process of neurogenesis, the progenitor cells of the cerebral cortex that give rise to neurons are the Radial Glia Cells (RGCs), and the cellular pathways regulating this process, are highly conserved across phylogeny. However, cortical size and complexity vary greatly across amniotes depending on the predominant mode of neurogenesis: Direct or Indirect. Reptiles (snakes) and birds (chick) produce most cortical neurons directly from apical RGCs (aRGCs) and develop a small, thin and simple cortex. In contrast, mammals predominantly produce cortical neurons indirectly through Intermediate Progenitor Cells (IPCs), resulting in a larger and more complex cortex with multiple neuronal layers. A precise balance between both types of neurogenesis is essential for proper cortical growth, both in development and evolution. Our previous work demonstrates that, contrary to the existing dogma, the process of neurogenesis undergoes a gradual transition during embryonic development, shifting from Indirect Neurogenesis at early stages to Direct Neurogenesis at late stages. Epigenomic and transcriptomic analyses of aRGCs in our model species (mouse, chick and snake) enabled us to identify candidate transcription factors regulating the choice of neurogenic modes, with particular interest in those elements that are highly conserved in amniotes. Among the multiple candidate genes identified as potential molecular regulators of the aRGC lineage and, consequently, defining cortical neurogenesis, we identify the transcription factor Sall1. Our experimental genetic manipulations in mouse and chick reveal an unsuspected, evolutionarily-conserved mechanism that regulates the mode of cortical neurogenesis, with important consequences on the development and architecture of the cerebral cortex.