Developmental gene expression patterns driving species-specific cortical features

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 used machine vision to identify and compare cell-type-specific gene expression patterns in the developing mouse and human neocortex, and in human cortical organoids. This identified genes with evolutionary conserved/divergent transcriptional regulation, revealing species-specific cyto-temporal gene expression patterns. Among such genes, the transcription factor JUNB showed mutually exclusive expression in human progenitors and mouse neurons. Through cell-type-specific gain- and loss-of-function experiments in mice and human organoids, we show that JUNB bidirectionally controls human cortical features, including progenitor proliferation rates, neuronal production timing, and total neuronal output. We identify IRF1 as a human RG-specific regulator that, when expressed in mouse RG, activates JUNB and recruits human-like gene regulatory networks, demonstrating cross-species activation of poised developmental programs. Together, these findings reveal how cyto-temporal regulation of shared genes drives species-specific cortical features and provides a molecular framework to understand and manipulate these evolutionary programs.