Progenitor Cell Diversity and Function in the Developing Cerebral Cortex

The human cerebral cortex, the largest structure of our brain, is the seat of our most highly developed cognitive functions. Its normal development, proper function, and ultimate size depend on a precisely controlled balance between self-renewal and differentiation of neural progenitor cells that reside in distinct germinal zones during development. Compared to other species, human cortical progenitor cells are exceptionally diverse in both cellular morphology and gene expression profile. In particular, previous work has identified specialized progenitors, called outer radial glia (ORG), that are especially common in humans yet virtually absent in rodents and other species with relatively smaller brains. This has led to the suggestion that ORG may represent targets of developmental mechanisms underlying the rapid evolutionary expansion of the human cortex. However, these cells have not been sufficiently profiled at the transcriptional level. To address this question, we combined cell type-specific sorting of cortical progenitor cells with transcriptome-wide RNA-sequencing (RNA-seq) to identify genes enriched in human ORG, which included several targets of the transcription factor Neurogenin as well as a surprising number of previously unknown, evolutionarily dynamic long noncoding RNAs (lncRNAs). We showed that activating the Neurogenin pathway in cortical progenitors of the ferret, a species with abundant ORG, promotes delamination and outward migration. We then used single-cell transcriptional profiling to compare patterns in human, ferret, and mouse progenitors, and found that a larger proportion of human RGC co-express proneural Neurogenin targets, suggesting greater self-renewal of neuronal lineage-committed progenitors in humans. Finally, comparative genomic analysis of several novel, human ORG-enriched long noncoding RNA genes indicated that many of these loci, while potentially present in the common ancestor of human, ferret, and mouse, show highly distinct patterns of ORG expression accompanied by greater genomic sequence divergence in rodents. Taken together, we find that the expansion of the ORG subpopulation and increased cortical size in humans is paralleled by increased transcriptional diversity of human RGC. Furthermore, we identify coding and noncoding genes that may be involved in human cortical progenitor identity, function, and evolution.Medical Science