Developmental gene expression patterns driving species-specific cortical features

Abstract The cerebral cortex shows species-specific variations in size and organization, likely accounting for distinct behavioral abilities. These structural differences may reflect evolutionary changes in the developmental expression of shared genes. To investigate this possibility, we compared cell-type-specific gene expression across species in the developing mouse and human neocortex, and human cortical organoids, by generating a shared transcriptional reference framework. This identified genes with conserved/divergent expression patterns, providing a molecular foundation to interrogate species-specific cellular properties. Using this resource, we discovered that the transcription factor JUNB is expressed in human but not mouse progenitors. Through cell-type-specific gain- and loss-of-function experiments in mice and human organoids, we demonstrate that JUNB bidirectionally controls human cortical features, including progenitor proliferation rates, neuronal production timing, and total neuronal output. This reveals how cell-type-specific regulation of shared genes during development can drive species-specific cortical features, providing a framework for understanding the molecular basis of cortical evolution.