Anoctamin 1 directs early radial glia fate towards somatostatin interneurons via GABA signaling

Neurogenesis and interneuron integration are crucial for maintaining cortical circuit functionality. In the medial ganglionic eminences (MGE), ventral radial glia (vRG) predominantly generates somatostatin-expressing (SST+) interneurons through direct neurogenesis in the neocortex. However, the mechanism guiding vRG to asymmetrically divide and produce either SST+ interneuron or intermediate progenitor (IP) remains unclear. This study identifies a novel subpopulation of vRG, characterized by the expression of Anoctamin 1/TMEM16a (ANO1), a Ca2+-activated Cl− channel predominantly found in Fabp7+/Sox2+ vRGs. ANO1 deficiency significantly reduces vRG proliferation, disrupting the ratio of SST+ interneuron to IP, and correlates with changes in the number of parvalbumin-expressing interneurons. Electrophysiological recordings from E12.5 brain slices reveal that ANO1 modulates GABA-dependent Ca2+ influx via Orai1. This regulation is essential for directing the production of SST+ interneuron or IP during mouse forebrain development. Our findings provide novel insights into the Ca2+ regulatory mechanisms mediated by ion channels, underlying early neural development.