UCSF

The human cerebral cortex is composed of a vast diversity of neuronal and glial cell types. Decades of work in animal models has informed a model of cortical development where neural stem cells that reside along the lateral ventricle first give rise to excitatory neurons followed by glial cell types including astrocytes and oligodendrocytes, while inhibitory cortical interneurons are born outside of the cortex and migrate in. However, it remains unclear to what degree human cortical development follows this canonical model. Recent work has demonstrated that during midgestation in humans this canonical population of ventricular radial glia differentiates into truncated radial glia that remain along the ventricle in the ventricular zone (VZ), and outer radial glia that form a second stem cell niche in the outer subventricular zone (OSVZ). In this thesis, I first use fate mapping of progenitors in the human VZ and OSVZ to demonstrate that these two stem cell niches give rise to spatially and morphologically distinct populations of astrocytes, and then use Patch-seq single cell analysis to identify unique molecular markers of these astrocyte subtypes. Second, I use a novel high throughput lineage tracing tool in combination with single cell RNA-sequencing to demonstrate that human cortical neural stem cells can give rise to both excitatory neurons and inhibitory cortical interneurons, and that these two cell types can be derived from the same individual stem cell. Together this work revolutionizes our understanding of both human cortical neurogenesis and gliogenesis and provides a foundation for understanding how these unique features of human cortical development may be perturbed in disease.