FOXG1 drives transcriptomic networks to specify principal neuron subtypes during the development of the medial pallium.

The medial pallium (MP) is the major forebrain region underlying learning and memory, spatial navigation, and emotion; however, the mechanisms underlying the specification of its principal neuron subtypes remain largely unexplored. Here, by postmitotic deletion of FOXG1 (a transcription factor linked to autism spectrum disorders and FOXG1 syndrome) and single-cell RNA sequencing of E17.5 MP in mice, we found that FOXG1 controls the specification of upper-layer retrosplenial cortical pyramidal neurons [RSC-PyNs (UL)], subiculum PyNs (SubC-PyNs), CA1-PyNs, CA3-PyNs, and dentate gyrus granule cells (DG-GCs) in the MP. We uncovered subtype-specific and subtype-shared FOXG1-regulated transcriptomic networks orchestrating MP neuron specification. We further demonstrated that FOXG1 transcriptionally represses Zbtb20 , Prox1 , and Epha4 to prevent CA3-PyN and DG-GC identities during the specification of RSC-PyNs (UL) and SubC-PyNs; FOXG1 directly activates Nr4a2 to promote SubC-PyN identity. We showed that TBR1, controlled by FOXG1 during CA1-PyN specification, was down-regulated. Thus, our study illuminates MP principal neuron subtype specification and related neuropathogenesis.