Temporal uncoupling of radial glia lineage progression in cortical organoids Stouffer, Melissa A Miranda, Osvaldo ; https://orcid.org/0000-0001-6618-6889 Pauler, Florian ; https://orcid.org/0000-0002-7462-0048 Pipicelli, Fabrizia Streicher, Carmen Cheung, Giselle T ; https://orcid.org/0000-0001-8457-2572 Hippenmeyer, Simon ; https://orcid.org/0000-0003-2279-1061 ddc:570 Radial glial progenitors (RGPs) produce all excitatory neurons in the developing cerebral cortex. Mosaic analysis with double markers (MADM)-based lineage tracing in vivo has revealed a quantitative framework of RGP lineage progression1. Here we established MADM technology2,3 in mouse embryonic stem cells to probe RGP lineage progression in a self-organizing cortical organoid system. We found that RGPs exhibit a high level of plasticity in proliferative potential in organoids rather than strict temporally stereotyped lineage progression as observed in vivo. RGPs in organoids showed increased lineage restriction, diminishing cell-type diversity in clones of cortical projection neurons, despite uniform single-cell transcriptional signatures of RGPs and a unitary lineage trajectory. Thus, critical non-cell-autonomous cues that are absent in self-organizing systems and/or the genuine stem cell niche are essential for faithful temporal control of RGP lineage progression and the generation of clonal cortical cell-type diversity. Springer Nature 2026 info:eu-repo/semantics/article doc-type:article text http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/22753 https://research-explorer.ista.ac.at/download/22753/22844 Stouffer MA, Miranda O, Pauler F, et al. Temporal uncoupling of radial glia lineage progression in cortical organoids. <i>Nature</i>. 2026. doi:<a href="https://doi.org/10.1038/s41586-026-10916-7">10.1038/s41586-026-10916-7</a> eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41586-026-10916-7 info:eu-repo/semantics/altIdentifier/issn/0028-0836 info:eu-repo/semantics/altIdentifier/e-issn/1476-4687 info:eu-repo/semantics/altIdentifier/pmid/42587153 info:eu-repo/semantics/openAccess