Dynamic landscapes of gene regulatory networks during early mammalian neurogenesis for understanding brain evolution and disorder risk

Neurogenesis is governed by dynamic transcriptional programs that vary across developmental time, brain region, and cell type, thereby forming regionally specialized neuronal circuits. However, the gene regulatory networks (GRNs) that coordinate these processes across species and brain regions are still not fully characterized. To address this, we construct a comprehensive GRN resource encompassing 24 neurogenic lineages from human, macaque, and mouse, enabling systematic cross-species and cross-regional comparisons. Integrated analyses characterize temporal regulatory dynamics and introduce a dynamic score to identify lineage-specific regulatory subnetworks, revealing hundreds of dynamic regulons and co-regulatory modules. We identify both known and novel candidate regulators that underlie neuronal differentiation and regional identity across the human brain and uncovered evolutionary divergence in neurogenic GRNs that distinguishes neurogenesis in humans from other species. Experimental characterization of the candidate neurogenic regulator ILF2 provides evidence for its role in neurogenesis. Furthermore, mapping disease-associated genes onto this resource reveals gene regulatory dynamics linked to 30 neurological disorders and traits, including autism spectrum disorder, schizophrenia, intellectual disability, and microcephaly. Our study provides a comprehensive cross-species and cross-regional atlas of neurogenic gene regulatory networks and their temporal dynamics. This resource facilitates the discovery of key regulators of early neuronal development, offers insights into the evolution of human brain regulatory programs, and enables the investigation of disease-associated regulatory mechanisms. The resource is freely accessible through an interactive online platform.