A conserved transcriptional axis links cortical organization, developmental timing and autism-associated perturbations

Abstract

Much of our mechanistic understanding of cortical development and neurodevelopmental disorders comes from studies in mice, yet translating these insights to humans rests on a fundamental assumption: that the cortex is organized according to conserved principles across species. Here, by independently decomposing human and mouse cortical transcriptomes, we test this assumption and identify a shared organizational axis extending from limbic anterior ventral (AV) to primary sensory posterior dorsal (PD) cortex. This axis aligns with conserved variation in cell-type composition, thalamocortical connectivity, myelination and excitation-inhibition balance. Its spatial topology emerges by mid-gestation and is progressively refined while remaining stable in orientation across subsequent development. What varies systematically along the axis is developmental timing: AV-enriched genes preferentially retained earlier cortical-construction features and progressively decline after birth, whereas PD-enriched genes preferentially reflected later maturation processes and progressively increased, with developmental rates graded along the axis. Across genetically distinct autism mouse models, developmental dysregulation converged on this axis, following a shared pattern that generally intensified toward the PD pole. The same axis also organized genotype-specific patterns of cortical volume alteration, while human autism risk genes showed corresponding enrichment along this transcriptional coordinate. Overall, we identify a conserved transcriptional axis that links cortical architecture to developmental timing and organizes the heterogeneous cortical effects of autism-associated mutations.