From Human Pluripotent Stem Cells to Cortical Circuits

Understanding the development of the human brain in relation with evolution is an important frontier field in developmental biology. In particular, investigating the mechanisms underlying the greatly increased relative size and complexity of the cerebral cortex, the seat of our enhanced cognitive abilities, remains a fascinating yet largely unsolved question. Though many advances in our understanding have been gained from the study of animal models, as well as human genetics and embryology, large gaps remain in our knowledge of the molecular mechanisms that control human cortical development. Interestingly, many aspects of corticogenesis can be recapitulated in vitro from mouse and human embryonic or induced pluripotent stem cells (PSCs), using a variety of experimental systems from 2D models to organoids to xenotransplantation. This has provided the opportunity to study these processes in an accessible and physiologically relevant setting. In this chapter, we will discuss how conserved and divergent features of primate/human corticogenesis can be modeled and studied mechanistically using PSC-based models of corticogenesis. We will also review what has been learned through these approaches about pathological defects of human corticogenesis, from early neurogenesis to late neuronal maturation and connectivity.