Comparative Genomics of Precursor Diversity and Function

ABSTRACT The neocortex is the most complex cellular system in the natural world, the seat of motor, sensory and executive function. While many of the mechanisms responsible for neocortical formation are known, key aspects of how gene expression and cellular behavior lead to species-specific features of the neocortex remain to be discovered. Recent advances in genomic analysis and in vivo cellular labeling enable study of cortical development at an unprecedented level of resolution. In particular, some human-specific genes and neural precursor cells have been detected and current evidence suggests that increased proliferative capacity and longer neurogenesis times enable the expanded growth of the primate neocortex. In this project using archived tissue, we will comprehensively compare the heterogeneous groups of neural precursor cells in mouse, macaque, chimpanzee and human neocortex. Using single cell and single nucleus RNA sequencing and implementation of novel molecular labeling tools, we will compare genomic signatures and in vivo behavior of these cells to uncover mechanisms of brain growth and evolution. A significant focus of this project will be on a precursor type called the basal radial glial cell (bRGC), thought to have emerged recently in evolution to enable expansion of the primate brain. However, our preliminary experiments uncover multiple groups of bRGCs in mouse neocortex that share key features of bRGCs found in primate brain, contradicting reports suggesting their biased role in primate brain growth. These studies will use emerging evidence and new tools to elucidate species-specific programs controlling neocortical growth.