BRN2 as a key gene drives the early primate telencephalon development

Evolutionary mutations in primate-specific genes drove primate cortex expansion. However, whether conserved genes with previously unidentified functions also play a key role in primate brain expansion remains unknown. Here, we focus on BRN2 (POU3F2), a gene encoding a neural transcription factor commonly expressed in both primates and mice. Compared to the limited effects on mouse brain development, BRN2 biallelic knockout in cynomolgus monkeys (Macaca fascicularis) is lethal before midgestation. Histology analysis and single-cell transcriptome show that BRN2 deficiency decreases RGC expansion, induces precocious differentiation, and alters the trajectory of neurogenesis in the telencephalon. BRN2, serving as an upstream factor, controls specification and differentiation of ganglionic eminences. In addition, we identified the conserved function of BRN2 in cynomolgus monkeys to human RGCs. BRN2 may function by directly regulating SOX2 and STAT3 and maintaining HOPX. Our findings reveal a previously unknown mechanism that BRN2, a conserved gene, drives early primate telencephalon development by gaining novel mechanistic functions.