Early emergence of projection-subtype fate-restricted radial glial progenitors orchestrates neocortical neurogenesis Varela-Martínez, I Villalba Requena, Ana ; https://orcid.org/0000-0002-5615-5277 Garcia-Marqués, J. Hippenmeyer, Simon ; https://orcid.org/0000-0003-2279-1061 Nieto, M. Radial glial progenitors (RGPs) generate all projection neurons (PNs) in the cerebral cortex through incompletely understood processes. Herein, we combine Mosaic Analysis with Double Markers (MADM)-based clonal analysis at embryonic days 12.5 and 13.5 with early postnatal callosal tracing to reveal a lineage progression that challenges the inside-outside model of cortical development and the conventional view of an invariable sequence of asymmetric neurogenic divisions. Our data demonstrate that early multipotent RGPs generate all extra-telencephalic (ET) and intra-telencephalic (IT) PNs across all layers through parallel sublineages and the random specification, during the earliest neurogenic divisions, of fate-restricted daughter RGPs. While the neuronal production of the parental multipotent RGPs consists of small ET-PN or IT-PN outputs, fate-restricted RGPs produce larger translaminar outputs spanning deep and upper layers of only IT-PNs, the predominant mammalian PN subtype. We further show that the emergence of IT-PN fate-restricted RGPs also leads to quantitatively and temporally stereotyped neurogenesis population-wise. 2025 info:eu-repo/semantics/preprint doc-type:preprint preprint http://purl.org/coar/resource_type/c_816b https://research-explorer.ista.ac.at/record/19717 Varela-Martínez I, Villalba Requena A, Garcia-Marqués J, Hippenmeyer S, Nieto M. Early emergence of projection-subtype fate-restricted radial glial progenitors orchestrates neocortical neurogenesis. <i>bioRxiv</i>. doi:<a href="https://doi.org/10.1101/2025.05.07.652665">10.1101/2025.05.07.652665</a> eng info:eu-repo/semantics/altIdentifier/doi/10.1101/2025.05.07.652665 info:eu-repo/semantics/openAccess