article epub_ahead yes Melissa A Stouffer author 4C9372C4-F248-11E8-B48F-1D18A9856A87 Osvaldo Miranda author 862A3C56-A8BF-11E9-B4FA-D9E3E56974250000-0001-6618-6889 Florian Pauler author 48EA0138-F248-11E8-B48F-1D18A9856A870000-0002-7462-0048 Fabrizia Pipicelli author 649134fd-d012-11ed-8f82-db1e5050f9ba Carmen Streicher author 36BCB99C-F248-11E8-B48F-1D18A9856A87 Giselle T Cheung author 471195F6-F248-11E8-B48F-1D18A9856A870000-0001-8457-2572 Simon Hippenmeyer author 37B36620-F248-11E8-B48F-1D18A9856A870000-0003-2279-1061 SiHi department Stem Cell Modulation in Neural Development and Regeneration/ P05-Molecular Mechanisms of Neural Stem Cell Lineage Progression project Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development project 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. https://research-explorer.ista.ac.at/download/22753/22844/2026_Nature_Stouffer.pdf application/pdfno Springer Nature2026 eng 0028-0836 1476-4687 4258715310.1038/s41586-026-10916-7 Stouffer, M. A., Miranda, O., Pauler, F., Pipicelli, F., Streicher, C., Cheung, G. T., &#38; Hippenmeyer, S. (2026). Temporal uncoupling of radial glia lineage progression in cortical organoids. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-026-10916-7">https://doi.org/10.1038/s41586-026-10916-7</a> M. A. Stouffer <i>et al.</i>, “Temporal uncoupling of radial glia lineage progression in cortical organoids,” <i>Nature</i>. Springer Nature, 2026. Stouffer, Melissa A, Osvaldo Miranda, Florian Pauler, Fabrizia Pipicelli, Carmen Streicher, Giselle T Cheung, and Simon Hippenmeyer. “Temporal Uncoupling of Radial Glia Lineage Progression in Cortical Organoids.” <i>Nature</i>. Springer Nature, 2026. <a href="https://doi.org/10.1038/s41586-026-10916-7">https://doi.org/10.1038/s41586-026-10916-7</a>. M.A. Stouffer, O. Miranda, F. Pauler, F. Pipicelli, C. Streicher, G.T. Cheung, S. Hippenmeyer, Nature (2026). 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> Stouffer, Melissa A., et al. “Temporal Uncoupling of Radial Glia Lineage Progression in Cortical Organoids.” <i>Nature</i>, Springer Nature, 2026, doi:<a href="https://doi.org/10.1038/s41586-026-10916-7">10.1038/s41586-026-10916-7</a>. Stouffer MA, Miranda O, Pauler F, Pipicelli F, Streicher C, Cheung GT, Hippenmeyer S. 2026. Temporal uncoupling of radial glia lineage progression in cortical organoids. Nature. 227532026-08-23T22:01:47Z2026-09-07T13:29:07Z