GenCortEvo

Genetic regulation of cortical stem cell lineages in amniote evolution

The cerebral cortex plays fundamental roles in our daily life, processing and integrating information from our outside and inner world to generate our behaviors and our higher cognitive functions. All mammals, birds and reptiles have a cerebral cortex, but there are enormous differences in size and cellular complexity among them. These differences emerged during evolution in a process recapitulated during embryonic development. Expansion of cortical size was possibly of key importance for the acquisition of higher neural functions, since patients with reduced cortical size display severe learning deficits, epilepsy and intellectual disability. Cerebral cortical neurons are born during embryonic development from neural stem cells. Radial Glia cells (RGCs) are the main class of neural stem cell, from which the rest of cell types derive. Whereas in reptiles RGCs have a limited proliferative capacity and generate neurons directly, in birds they have a greater proliferative capacity and, in a small proportion, generate neurons indirectly, via Intermediate Progenitor Cells (IPCs). In mammals, RGC proliferation is maximal and they generate large amounts of IPCs and other types of intermediate stem cells, producing massive amounts of cortical neurons, which culminates in the human brain. The goal of this project is to investigate which genomic changes occurred during amniote evolution, from reptiles to humans, modifying the biology of RGCs and their cellular lineage, to amplify their neuronal production and expand the size of the cerebral cortex. Our recent discoveries show that the lineage and mode of neurogenesis of RGCs depend on the activity level of molecular signaling cascades that are conserved in phylogeny, such as Robo. This indicates that the evolutionary expansion of the cerebral cortex was largely based on the modification of mechanisms that regulate gene expression levels. This project follows an innovative strategy based on using a unique combination of species spanning amniote phylogeny and the diversity of their cortical phenotypes, and which naturally recapitulate the evolutionary expansion of the cerebral cortex: African house snake, chick, mouse, ferret and human. Our findings from this project will provide fundamental information about the mechanisms of human brain evolution, while also identifying risk factors for anomalies of human brain development, with dramatic consequences on its function.