Identification of TGFβ signaling as a regulator of interneuron neurogenesis in a human pluripotent stem cell model

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 transforming growth factor β (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, the present study represents a useful platform for studying human interneuron development and interneuron-associated neurological diseases with human pluripotent stem cells.