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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325956 | GEO | 2026/03/25

REPOSITORIES: GEO

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Project description:We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex. For study version 2, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections. For study version 3, we have updated the data set to include additional primary cells, including those published in Nowakowski, et al., Science 2017: "Spatiotemporal Gene Expression Trajectories Reveal Developmental Hierarchies of the Human Cortex" (in press)

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

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