“These combined, extensive measurements provided us with a first dynamic view of the symphony of molecular events that unfold as this critical region of the brain is built in the embryo,” said Arlotta, who is also an institute member in the Stanley Center for Psychiatric Research at the Broad Institute. “Researchers have been studying the process of development of the cerebral cortex for over a century, but the mechanistic events that govern how cells are made and how they interact to ultimately form functional circuit have remained elusive. As a field, we have historically looked at this complex developing tissue one cell type at a time and investigated small numbers of genes for their roles in putting together pieces of this amazing puzzle. But the brain does not develop one cell type at the time — it is truly a symphony in the sense that hundreds of cell types undergo development together, using ever-changing landscapes of genes to form the adult tissue. Now imagine having for the first time the full ‘recipe’ of genes that any given cell class uses as its development unfolds. Imagine also gaining detailed knowledge of the ‘codes of genes’ that turn on or off as distinct lineages of cells separate from each other and get built. This type of overarching mechanistic knowledge offers an opportunity to study cortical development in a brand new way, looking at all cells and all genes. We never had information this complete before and I must admit that I stared at the data in awe, thinking about the type of discovery that it enables.”

“Ten years ago, this study would not have been possible because the technologies either did not exist or were not mature enough yet,” Regev said. “But with advances in single-cell and spatial transcriptomics, and new machine learning algorithms for large data analysis, we were able to map where cells develop, put those maps together, and watch development unfold like a movie over time. We could not only reconstruct the movie but could also link that picture to a greater biological understanding of brain development. We hope this approach could one day help us better understand and treat diseases of the brain.”

Arlotta added: “It is a pretty interesting movie — one that I have looked forward to filming for most of my scientific career.”

This research was supported by the Stanley Center for Psychiatric Research, the Broad Institute of MIT and Harvard, the P50 Conte Center (5P50MH094271 Developmental origins of mental illness: evolution and reversibility), the National Institutes of Health (5U19MH114821, 5R01NS103758, DP5OD024583), the Klarman Cell Observatory, HHMI, and an NHGRI Center for Cell Circuits CEGS grant.