UCSF

During development of the cerebral cortex, progenitors give rise to diverse cell types in a spatially and temporally defined fashion, but the fate competence of individual progenitors and the lineage relationships between mature cell types has been difficult to ascertain. In this dissertation, I apply a novel prospective lineage tracing tool utilizing synthetic DNA barcodes to label human cortical progenitors and their resulting daughter cells in order to profile their output throughout neurogenesis. First, I show that cortical progenitors are capable to produce inhibitory interneurons, a cell type that had previously been widely believed to derive only from the ventral ganglionic eminences. In an in vitro model as well as in a xenotransplantation model, individual progenitors give rise to both excitatory and inhibitory neurons. Next, I extend this approach to more thoroughly analyze the temporal dynamics of cortical neurogenesis. Lineage tracing across the late second trimester reveals that inhibitory neurogenesis from dorsal progenitors is not a constant feature of cortical development, but arises prominently after midgestation. Furthermore, I show that excitatory neurogenesis proceeds at the ventricular zone throughout development, particularly by a subset of radial glia known as truncated radial glia. These excitatory neurons include neurons of deep layer identity, which are born throughout the second trimester, not just at early timepoints as had been previously believed. Together, these results shed light on previously unappreciated aspects of human cortical neurogenesis and highlight the diverse lineage potential of individual cortical progenitors.