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Genetic links between development and evolution of the human cerebral cortex

Final Report Summary - GENDEVOCORTEX (Genetic links between development and evolution of the human cerebral cortex)

What makes the human brain unique? With GENDEVOCORTEX we have tested the radical hypothesis that new genes, emerging selectively during human evolution, play a major role in the development of the cerebral cortex, the most complex structure in the human brain. In this projet we have first examined which genes are active during human ccorticogenesis, with special focus on those that are thought to result from gene duplication during the evolution of hominids (human and great apes). This has enabled us to discover of more than 30 genes that are only present in the human or hominid genomes, and that are uniquely expressed in the human developing cerebral cortex. We have then tested their function using animal models and models of human brain development based on human embryonic stem cells. In particular we have discovered the Notch2NL genes that we found to control the expansion of neural stem cells of the cortex, and thereby the expanded size of the human cerebral cortex. Moreover we found that many of the human-specific genes are located in regions of the human genome that are associated with copy number variant leading to brain diseases such as microcephaly, macrocephaly, and autism spectrum disorders. Our work has thus enabled to link functionally the development and the evolution of the human brain, as well as neurodevelopmental diseases. It also led to the development of new technologies combining pluripotent stem cells and brain xenotransplantation to study human brain development, which opens entirely new opportunities for the modelling of human brain diseases, but also for the longer term prospect of cell therapy for brain damage or degeneration.