An Integrative Definition of Cell Types During Human Cortical Neurogenesis
Nowakowski TJ1, Bhaduri A1, Pollen AA1, Sandoval-Espinosa C1, Chen J1, Velmeshev D1, DiLullo E1, Kriegstein AR1,2*.
1Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; 2Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
We initially used single cell approaches to establish an integrative definition of progenitor cells in the developing neocortex based on position, morphology, cell behavior, developmental potential, and gene expression. By analyzing gene expression across single cells, we found that oRG cells preferentially express genes related to extracellular matrix formation, migration, and stemness, and we related these genes to the position, morphology, and behaviors previously used to classify these cells. Many of these genes are involved in growth factor signaling and self-renewal pathways, suggesting that outer radial glia cells establish a self-sustaining proliferative niche. More generally, we have expanded this approach to identify the genes and pathways distinguishing diverse cell types during cortical development. We have now identified over 20 molecularly distinct cell states during cortical development spanning known and novel features of cell diversity. These cell states highlight age and region specific programs, and offer unique insights into transcriptional pathways that drive cortical development. Using our single cell map of molecular diversity during cortical development, we can highlight cell types that are uniquely vulnerable to neurodevelopmental disorders, including our prediction and subsequent demonstration that Zika virus preferentially infects radial glia, astrocytes, and microglia using AXL as an entry factor, illustrating the utility of our cell genomic map. Towards the goal multimodal analysis of single cells, we have recently begun incorporating other single cell parameters to expand the definitions of cell type classification.