FOXG1 spatiotemporally orchestrates subtype fate specification and patch/matrix identity of striatal spiny projection neurons

The striatum consists of three main spiny projection neuron subtypes, direct-pathway neurons (dSPNs), indirect-pathway neurons (iSPNs), and recently identified eccentric striatal neurons (eSPNs) with these SPNs organized into two complementary compartments, the patch and the matrix. However, the cellular basis underlying subtype specification especially that of eSPNs, and mechanisms governing the complementary patterning remain unclear. Here, employing single-cell RNA sequencing (scRNA-seq) combined with loss-of-function we reveal that eSPNs share more developmental similarities with iSPNs and the transcription factor Foxg1 promotes dSPN and iSPN fates but suppresses eSPN fate in ventral region of the lateral ganglionic eminence lineage. Deletion of Foxg1 in progenitors forces both dSPNs and iSPNs into an eSPN fate. While postmitotic Foxg1 deletion impairs patch/matrix identity and leads to SPN aggregation. We identify FOXG1-driven transcriptional programs and key transcription factors that specify each striatal SPN subtype and patch/matrix identity, and uncover FOXG1 directly regulated cell migration- and cell adhesion-related molecules that control SPN migration. Our findings provide insights into striatal development.