<i>BRN2</i> as a key gene drives the early primate telencephalon development.

Abstract

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