Here we present a small molecule-based strategy for the efficient induction of human cortical interneurons. Exposure to the tankyrase inhibitor XAV939 enhances forebrain differentiation. Using an NKX2.1::GFP hESC reporter line, we demonstrate the selective derivation of three distinct ventral forebrain precursor populations by combining XAV939 treatment with the timed activation of SHH signaling. Importantly, results in both hPSCs and in human embryos reveal differences between mouse and human forebrain development such as the human-specific, yet transient, FOXA2 expression within the ventral forebrain. Finally, mature functional properties and expression of late cortical interneuron markers, including parvalbumin and somatostatin, demonstrate the feasibility of studying human cortical interneuron differentiation from hPSCs in vitro despite their protracted development in vivo.
