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 Dmrta2 in NPCs suppresses differentiation without affecting their neurogenic competence. In contrast, Dmrta2 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 Hes1 and other proneural genes, as demonstrated by genome-wide RNA-seq and direct binding of Dmrta2 to the Hes1 genomic locus. Moreover, transient Hes1 expression rescues precocious neurogenesis in Dmrta2 knockout NPCs. Our study thus establishes a link between Dmrta2 modulation of Hes1 expression and the maintenance of NPCs during cortical development.Dmrta2 | Hes1 | cell cycle | transcription factor | neurogenesis

Cortical interneurons are GABAergic inhibitory cells that connect locally in the neocortex and play a  pivotal role in shaping cortical network activities. Dysfunction of these cells is believed to lead to runaway excitation underlying seizure-based diseases, such as epilepsy, autism, and schizophrenia. There is a growing interest in using cortical interneurons derived from human pluripotent stem cells for understanding their complex development and for modeling neuropsychiatric diseases. Here, we report the identification of a novel role of TGFβ signaling in modulating interneuron progenitor maintenance and neuronal differentiation. TGFβ signaling inhibition suppresses terminal differentiation of interneuron progenitors while exogenous TGFβ3 accelerates the transition of progenitors into postmitotic neurons. We provide evidence that TGFb signaling exerts this function via regulating cell cycle length of the NKX2.1+ neural progenitors. Together, this study represents a useful platform for studying human interneuron development and interneuron associated neurological diseases with human pluripotent stem cells.