Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain.

Different functional regions of brain are fundamental for basic neurophysiological activities. However, the regional specification remains largely unexplored during human brain development. Here, by combining spatial transcriptomics (scStereo-seq) and scRNA-seq, we built a spatiotemporal developmental atlas of multiple human brain regions from 6-23 gestational weeks (GWs). We discovered that, around GW8, radial glia (RG) cells have displayed regional heterogeneity and specific spatial distribution. Interestingly, we found that the regional heterogeneity of RG subtypes contributed to the subsequent neuronal specification. Specifically, two diencephalon-specific subtypes gave rise to glutamatergic and GABAergic neurons, whereas subtypes in ventral midbrain were associated with the dopaminergic neurons. Similar GABAergic neuronal subtypes were shared between neocortex and diencephalon. Additionally, we revealed that cell-cell interactions between oligodendrocyte precursor cells and GABAergic neurons influenced and promoted neuronal development coupled with regional specification. Altogether, this study provides comprehensive insights into the regional specification in the developing human brain.

Decoding the temporal and regional specification of microglia in the developing human brain.

Region-related heterogeneity and state transitions of microglia are important for brain development and neurological pathogenesis. However, regional specialization and state transition in microglia during early human CNS development remain unclear. Here, we profile single-cell transcriptomes of microglia from distinct regions of the developing human brain, and combined with experimental verification, we define and characterize early microglial fate determinations related to regional specification and state transition. We identified several subclasses of neuronal gene-enriched microglia with regional specification that dynamically and transiently appeared as early brain regions formed. In contrast, immune-related microglia were regionally specialized at later stages of CNS development. Surprisingly, we discovered that region-specialized immune-related microglia exit from a relative resting state and transition into distinct active states. In addition, we experimentally verified the microglial state transition. Finally, we showed that the state transition is conserved but that there are molecular differences in developing microglia in humans and mice.