Thalamic NRXN1-Mediated Input to Human Cortical Progenitors Drives Excitatory Neurogenesis

According to the protocortex hypothesis, extrinsic thalamic signaling is necessary for refining cortical areas and cell types, but the mechanism by which these inputs shape human cortex development remains largely unexplored. We fuse cortical and thalamic organoids to study this process. Using single-nuclei RNA-sequencing and cellular imaging, we discover that thalamic signals during a progenitor-rich critical period drive developmental gene expression changes and shift cell fate toward increased excitatory neurogenesis. We find NRXN1 mediates thalamic axon contact with primate-enriched outer radial glia; genetic perturbation of NRXN1 reduces these contacts and significantly attenuates upper-layer neurogenesis. These findings underscore the influence of thalamic input on human cortical radial glia specification, and suggest a novel mechanism for thalamic regulation of human outer radial glia cell fate.