The molecular and cellular mechanisms of human brain expansion.

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The rapid evolutionary expansion of the human brain, in particular the cerebral neocortex, is the structural foundation of our unique intellectual abilities. The extraordinary size and extensively folded shape of the human brain makes it distinct from the brains of other mammals, including our primate relatives. During fetal development, neural stem cells undergo highly controlled proliferation and differentiation processes to generate the neurons and glia that make up the postnatal brain. It has been hypothesized that changes in the behaviours of human neural stem cells may be directly responsible for the expansion and folding of the human brain. In particular, distinct subtypes of neural stem cells that are abundant in the primate brains but absent in the mouse brains may contribute to brain expansion in the primate lineage. However, these hypotheses are largely untested, due to the inaccessible nature of the fetal human and non-human primate brains. As a result, our knowledge of the molecular and cellular mechanism that underlies human brain expansion remains extremely limited. My previous research has shown that crucial steps of human brain formation can be mimicked in the dish, thereby circumventing the need of human fetal tissues. We achieved this by deriving pluripotent stem cells from human skin cells, and then differentiating these stem cells into neurons and brain organoids. In the proposed research, my team will apply this strategy to create an innovative multi-species stem cell platform to study brain development in human, non-human primates, and mouse. We anticipate that the direct comparison of neural cells and brain organoids from human (a primate with large, folded brain), macaque (a primate with intermediate, folded brain), marmoset (a primate with small, smooth brain), and mouse (a rodent with very small, smooth brain) will provide unprecedented insights into the molecular, cellular, and anatomical mechanisms that regulate brain expansion and folding. The strategies, techniques, and infrastructure used in my research program will provide HQPs with cutting-edge training in stem cell engineering, gene editing, genomics analysis and high throughput assays. Understanding how the human brain forms and what makes it unique is the cornerstone for understanding who we are. Discoveries made in this work will advance the fields of stem cell biology and neurobiology, as well as have broad impact on studies of human biology.