hPSC Modeling Reveals that Fate Selection of Cortical Deep Projection Neurons Occurs in the Subplate

Cortical deep projection neurons (DPNs) are implicated in neurodevelopmental disorders. Although recent findings emphasize post-mitotic programs in projection neuron fate selection, the establishment of primate DPN identity during layer formation is not well understood. The subplate lies underneath the developing cortex and is a post-mitotic compartment that is transiently and disproportionately enlarged in primates in the second trimester. The evolutionary significance of subplate expansion, the molecular identity of its neurons, and its contribution to primate corticogenesis remain open questions. By modeling subplate formation with human pluripotent stem cells (hPSCs), we show that all classes of cortical DPNs can be specified from subplate neurons (SPNs). Post-mitotic WNT signaling regulates DPN class selection, and DPNs in the caudal fetal cortex appear to exclusively derive from SPNs. Our findings indicate that SPNs have evolved in primates as an important source of DPNs that contribute to cortical lamination prior to their known role in circuit formation. [Display omitted] •Subplate neurons (SPNs) in vitro can generate cortex deep projection neurons (DPNs)•SPNs in fetal cortex express multiple markers of DPNs and enter the cortical plate•WNT signaling regulates post-mitotic projection neuron identity of SPNs•SPNs in the caudal cortex are the only cells enriched in corticofugal neuron genes Ozair et al. show that major classes of cortical DPNs can be specified from subplate neurons (SPNs) derived from hPSCs by modulating post-mitotic WNT signaling. The findings indicate that SPNs have evolved in primates as an important contributor to cortical lamination. These findings have implications for understanding neurodevelopmental disorders.