DISSECTING THE TRANSCRIPTOMIC IDENTITY OF BRG DURING NEOCORTICAL DEVELOPMENT AND EVOLUTION: FROM MORPHOLOGY TO METABOLISM AND DISEASE

Basal radial glia (bRG) play a crucial role in neocortical development by regulating the production and migration of cortical neurons. Interestingly, neurogenic potential and neuronal migration are highly dependent on bRG morphology, with more complex morphotypes exhibiting higher neurogenic and scaffolding potentials. Although the link between proliferative capacity and morphological heterogeneity is becoming increasingly evident, mechanisms underlying this relationship are poorly understood. To investigate the mechanism underlying the proliferative capacity and morphology of bRG in human cortical organoids, we knocked out ADD1, a known morphoregulatory gene. Our results demonstrate that ADD1 regulates cell fate of radial glia, and is required for correct progression of neurogenesis during neocortical development. In parallel, due to its poor characterization, in this PhD thesis, we also investigated the transcriptomic profile of bRG, and identified novel morphoregulatory and metabolic players distinguishing bRG from other cell populations, as well as genes linked to malformations of cortical development, a group of rare but severe disorders of neocortical development. Finally, we placed bRG in the evolutionary context by exploring their transcriptomic signature across the developing human and mouse neocortex, and mouse dentate gyrus. Remarkably, our results suggested that bRG in the mouse dentate gyrus are transcriptionally more resembling those in human neocortex than mouse neocortex. These findings contest the traditional hypothesis supporting the view that highly specialized bRG traits might have existed in the common ancestor of all placental mammals, but were subsequently abandoned in some mammals. Overall, this PhD Thesis brings novel insights into the developmental and evolutionary role of bRG cells, and reports molecular players involved in distinct morphological, metabolic and cytoprotective behavior of bRG.