Directed Migration of Cortical Interneurons Depends on the Cell-Autonomous Action of Sip1

GABAergic interneurons mainly originate in the medial ganglionic eminence (MGE) of the embryonic ventral telencephalon (VT) and migrate tangentially to the cortex, guided by membrane-bound and secreted factors. We found that Sip1 (Zfhx1b, Zeb2), a transcription factor enriched in migrating cortical interneurons, is required for their proper differentiation and correct guidance. The majority of Sip1 knockout interneurons fail to migrate to the neocortex and stall in the VT. RNA sequencing reveals that Sip1 knockout interneurons do not acquire a fully mature cortical interneuron identity and contain increased levels of the repulsive receptor Unc5b. Focal electroporation of Unc5b-encoding vectors in the MGE of wild-type brain slices disturbs migration to the neocortex, whereas reducing Unc5b levels in Sip1 knockout slices and brains rescues the migration defect. Our results reveal that Sip1, through tuning of Unc5b levels, is essential for cortical interneuron guidance. ► Sip1 is crucial for directed cortical interneuron migration ► RNA sequencing identifies Sip1-dependent differentiation and guidance factors ► Sip1 is essential to constrain the expression level of Unc5b in the MGE ► Tuning of Unc5b expression level regulates the direction of interneuron migration Van den Berghe et al. demonstrate that Sip1 (Zfhx1b, Zeb2), a transcription factor enriched in migrating cortical interneurons, controls their differentiation and directed migration. Through regulating Unc5b expression, Sip1 contributes to efficient guided migration during brain development in the embryo.