UC Santa Cruz

Understanding what makes us human is a major goal in biology. Humanity is marked by our ability to learn from the lessons of our ancestors; a capacity that was bestowed on us through the evolution of our cerebral cortex. An expansion of our forebrain has undergone a 4-fold expansion over the last 3.5 million years. Neurodevelopmental evidence points to gene duplications in the 1q21.1 region as contributing to human specific differences in cranial volume. This thesis aims to further the goal of understanding the evolution of human brain development through two fronts. First, combining genetically engineered knockouts of regions of 1q21.1 with stem cell derived models of the developing brain and single cell transcriptome sequencing we provide evidence of the role of NOTCH2NL in stem cell maintenance and lineage choice. NOTCH2NL knockout cell lines demonstrate decreases in the number of late derived neurons as well as a population of cells in the osteoblast lineage expressing PDGFRB and lacking PDGFRL expression. This suggests that by accelerating late neurogenesis and increasing skull bone production, NOTCH2NL is the causative mutation in 1q21.1 neurodevelopmental pathologies. Second, we engineer physical automation tools around stem cell derived models of the developing brain to better mimic physiology in these models. We show that our model augments the expression of glycolysis pathway genes towards expression levels found in the human body, potentially fixing the biggest observed differences in traditional cerebral organoid models from their physiological counterparts.