Orchestrated molecular changes of proliferative, migratory‐fibrillar, synaptic, and postmigratory compartments align with precocious cortex‐type specification in the early human pallium

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Early development of the human pallium is shaped by transient cellular compartments that regulate the emergence of cytoarchitectonically distinct cortical types. At these stages, regional identity depends less on mature cortical layers-which form later in gestation-and more on the organization of transient compartments spanning from the pia to the ventricular surface. These early compartments arise within separate pallial sectors, including the medial pallium that produces the archicortex and mesocortex and the dorsal pallium that expands into the neocortex. Although recent studies have described molecular and cellular features within individual compartments, the spatiotemporal relationships among them that govern cortex-type specification remain insufficiently understood. We analyzed the distribution of proliferative, neuronal, fibrillar, and synaptic markers across the ventricular zone (VZ), subventricular zone (SVZ), cortical plate (CP), subplate (SP), and marginal zone (MZ) in prospective neocortical, mesocortical, and archicortical regions of the human fetal pallium. Development was examined across key phases: late preplate (7.5 PCW), initial CP formation (8 PCW), first CP condensation (9.5-12 PCW), SP formation (13-14 PCW), and the onset of typical fetal lamination (15 PCW). During the preplate phase, an expanded plexiform MZ containing the earliest TBR2+ and TBR1+ cells, along with tangential medial fibers, delineates the emerging archicortical (hippocampal) and mesocortical (entorhinal) sectors, which occupy much of the interhemispheric pallium. In contrast, the dorsal isocortical pallium shows a broad influx of TBR1+ neurons through abventricular compartments, while in the hippocampal primordium, these cells remain confined to the superficial zone. By 8 PCW, the first prospective pyramidal neurons form a disk-shaped CP in the midlateral neopallium, with a basal-to-dorsal gradient reflecting SVZ proliferative activity. At the same time, the ventral archicortex shows a distinct pattern characterized by MZ expansion, accumulation of "dormant" TBR2+ cells, absence of a defined CP, and progressive merging of the SVZ and MZ. Between 9.5 and 12 PCW, with the onset of the second proliferative wave, a CP emerges in the ventral hippocampal anlage. The future entorhinal mesocortex differentiates unusually early, displaying large multipolar "promoter" neurons in the superficial CP and the first appearance of a fibrillar lamina dissecans. By 13 PCW, hippocampal fields are discernible, and in the neocortex, the major developmental event is SP formation through merging of the deep CP and presubplate. Although hippocampal CP formation initially lags behind that of the neopallium, its subsequent differentiation-and that of adjacent transitional cortices-is accelerated. By 15 PCW, prospective archicortical, mesocortical, and neocortical sectors are clearly recognizable. Our findings suggest that cortex-type divisions arise from coordinated interactions among proliferative, migratory-fibrillar, synaptic, and postmigratory compartments. Allocortical regions exhibit distinctive developmental trajectories, including MZ enlargement, tapering of SVZ and SP and a characteristic tempo of CP formation. This compartment-based perspective highlights early transitional belt-like zones and spatiotemporal gradients across the pallium and identifies the ventral mesocortical (prospective entorhinal) area as an early organizing hub at the interface of allocortical and transmodal connectivity.

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