Comparative transcriptomics reveals shifts in cortical architecture at the metatherian/eutherian transition
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The neocortex, a layered structure unique to mammals, supports higher-order functions such as perception, learning, and decision-making. While its overall organization is broadly conserved, it remains unclear whether changes to the cell type-specific organization of the cortical column—the basic unit of cortical processing— occurred at the metatherian/eutherian split. To address this, we used single-nucleus RNA sequencing and spatial transcriptomics to compare gene expression, cell types, and laminar architecture in the primary visual cortex of a metatherian ( Monodelphis domestica ) and a eutherian mammal ( Mus musculus ). We find distinctions between supragranular (layer 2/3) and infragranular (layers 5 and 6) intratelencephalic (IT) neurons to be more pronounced in mice, with layer 2/3 neurons enriched for transcripts involved in synaptic transmission, adhesion, and dendritic development. Mouse cortex also exhibits expanded populations of disinhibitory interneurons, redistribution of perineuronal nets, and reduced oligodendrocyte density—features known to enhance cortical plasticity. These findings suggest the metatherian–eutherian split was accompanied by remodeling of the cortical column, highlighting potential substrates of neocortical evolution in early mammals.
Significance Statement
The neocortex is central to perception and flexible behaviors in mammals, yet its evolutionary origins remain unclear. By comparing cell types and spatial organization in visual cortex of marsupials and placental mammals, we found that key neuron classes— especially those involved in intracortical communication—became more specialized and spatially distinct in placentals. These changes are paralleled by shifts in inhibitory circuitry and myelinating cells, suggesting an evolutionary trajectory favoring increased cortical plasticity. Our findings challenge the long-held view that cortical columns are tightly conserved and shed light on the cellular substrates of early neocortical evolution.
