The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1

Abstract

The mechanisms that determine whether a neural progenitor cell (NPC) reenters the cell cycle or exits and differentiates are pivotal for generating cells in the correct numbers and diverse types, and thus dictate proper brain development. Combining gain-of-function and loss-of-function approaches in an embryonic stem cell-derived cortical differentiation model, we report that doublesex- and mab-3-related transcription factor a2 (Dmrta2, also known as Dmrt5) plays an important role in maintaining NPCs in the cell cycle. Temporally controlled expression of transgenic <i>Dmrta2</i> in NPCs suppresses differentiation without affecting their neurogenic competence. In contrast, <i>Dmrta2</i> knockout accelerates the cell cycle exit and differentiation into postmitotic neurons of NPCs derived from embryonic stem cells and in Emx1-cre conditional mutant mice. Dmrta2 function is linked to the regulation of <i>Hes1</i> and other proneural genes, as demonstrated by genome-wide RNA-seq and direct binding of Dmrta2 to the <i>Hes1</i> genomic locus. Moreover, transient <i>Hes1</i> expression rescues precocious neurogenesis in <i>Dmrta2</i> knockout NPCs. Our study thus establishes a link between Dmrta2 modulation of <i>Hes1</i> expression and the maintenance of NPCs during cortical development.