Neocortical Projection Neurons Instruct Inhibitory Interneuron Circuit Development in a Lineage-Dependent Manner

Neocortical circuits consist of stereotypical motifs that must self-assemble during development. Recent evidence suggests that the subtype identity of both excitatory projection neurons (PNs) and inhibitory interneurons (INs) is important for this process. We knocked out the transcription factor Satb2 in PNs to induce those of the intratelencephalic (IT) type to adopt a pyramidal tract (PT)-type identity. Loss of IT-type PNs selectively disrupted the lamination and circuit integration of INs derived from the caudal ganglionic eminence (CGE). Strikingly, reprogrammed PNs demonstrated reduced synaptic targeting of CGE-derived INs relative to controls. In control mice, IT-type PNs targeted neighboring CGE INs, while PT-type PNs did not in deep layers, confirming this lineage-dependent motif. Finally, single-cell RNA sequencing revealed that major CGE IN subtypes were conserved after loss of IT PNs, but with differential transcription of synaptic proteins and signaling molecules. Thus, IT-type PNs influence CGE-derived INs in a non-cell-autonomous manner during cortical development. •IT-type projection neurons influence the lamination of CGE-derived interneurons•Converting IT-type cells to PT type disrupts CGE interneuron synaptic connections•PT-type projection neurons do not target CGE interneuron subtypes in deep layers•Loss of IT-type cells alters gene transcription in CGE cells but not major subtypes Neocortical circuits are comprised of intermingled excitatory projection neuron and inhibitory interneuron subtypes. Wester et al. show that fate-switching corticocortical projection neurons to a subcerebral type selectively influences the lamination, circuit integration, and gene transcription of CGE-derived interneurons.