Initial regional cytoarchitectonic differences in dorsal and orbitobasal human developing frontal cortex revealed by spatial transcriptomics

Early development of the human fetal cerebral cortex involves a set of precisely coordinated molecular processes that remains rather underexplored. Previous studies indicate that the laminar identity and the molecular specification of cortical neurons driven by genetic programming, as well as associated histogenetic events begin during early fetal development. Our recent study discovered unique regional cytoarchitectonic features in the developing human frontal lobe, including migratory waves of postmitotic neurons in the dorsal frontal cortex and the "double plate" feature in orbitobasal cortex (Kopić et al. in Cells 12:231, 2023). Notably, neurons of these two cytoarchitectonic features typically express deep projection neuron (DPN) markers (TBR1, TLE4, SOX5). This paper aims to conduct an in-depth investigation of these cytoarchitectonic features at the transcriptomic level, whilst preserving spatial information. Here, we employed NanoString GeoMx^™ Digital Spatial Profiler (DSP) technology to examine gene expression differences in the transient cortical compartments of the dorsal and ventral regions of the developing frontal lobe, focusing specifically on 15 post-conceptional weeks (PCW), that is a critical period for subplate formation. We identified multiple differentially expressed genes between the transient cellular compartments of the dorsal and orbitobasal regions of the developing human frontal cortex. These new findings additionally confirm that regional patterning and specification of the prospective higher-order association prefrontal cortex emerges early in fetal development, contributing to the highly organized cortical architecture of the human brain.