The goal of this research proposal is to unravel the molecular and cell biological basis underlying the expansion of the human cerebral cortex. Specifically, we wish to identify the genes responsible for the increase in the generation of cortical neurons from neural stem and progenitor cells that occurs during primate evolution. We will take two complementary approaches. One is to characterize the differences between mouse and human cerebral cortex with regard to the molecular and cell biological features of neural stem and progenitor cells, their mode of division, and the generation of neurons from these cells. Among the observed differences, human-specific features of cortical progenitor cells will then be identified by comparison with various non-human primates. The resulting candidate genes will be expressed in mouse embryonic cortical progenitors by in utero electroporation and tested for their ability to reconstitute human-like cortical progenitors in vivo. The second approach is based on a novel technology that allows us to introduce the total pool of mRNAs expressed in human cortical progenitors into mouse cortical progenitors in organotypic slice culture. This technology will be used to functionally screen for human genes able to generate human-like cortical progenitors in the mouse embryonic cortex. Human genes validated by these two approaches will then be used to generate acute transgenic mouse embryos and transgenic mouse lines that show a gyrencephalic, primate-like cerebral cortex. This research proposal will provide fundamental insight into the process of human cortical expansion, which provides the cellular basis of higher brain function, and establish an essential basis for future progenitor cell-based therapies for the diseased human brain.