Molecular Lineages and Spatial Distributions of Subplate Neurons in the Human Fetal Cerebral Cortex

Abstract The expansion of neural progenitors and production of distinct neurons are crucial for architectural assembly and formation of connectivity in human brains. Subplate neurons (SPNs) are among the firstborn neurons in the human fetal cerebral cortex, and play a critical role in establishing intra‐ and extracortical connections. However, little is known about SPN origin and developmental lineages. In this study, spatial landscapes and molecular trajectories of SPNs in the human fetal cortices from gestational weeks (GW) 10 to 25 are created by performing spatial transcriptomics and single‐cell RNA sequencing. Genes known to be evolutionarily human‐specific and genes associated with extracellular matrices (ECMs) are found to maintain stable proportions of subplate neurons among other neuronal types. Enriched ECM gene expression in SPNs varies in distinct cortical regions, with the highest level in the frontal lobe of human fetal brains. This study reveals molecular origin and lineage specification of subplate neurons in the human fetal cerebral cortices, and highlights underpinnings of SPNs to cortical neurogenesis and early structural folding.