biostudies-literatureShen DThe National Key Research and Development Project of ChinaThe Collaborative Innovation Program of Shanghai Municipal Health CommissionSTI2030 Major ProjectsMOST | National Key Research and Development Program of China (NKPs)MOST | National Natural Science Foundation of China (NSFC)The Shanghai Municipal Science and Technology Major ProjectMOST | National Key Research and Development Program of ChinaThe Foundation of Shanghai Municipal Education CommissionMOST | National Natural Science Foundation of China182-209https://www.ebi.ac.uk/biostudies/studies/S-EPMC12759082biostudies-literatureUnknown45(1)The size and complexity of the neocortex are largely determined during brain development by neurogenesis from radial glial progenitor (RGP) cells. Neurogenesis from such cells can be direct (i.e., RGP cells give rise directly to neurons) or indirect (i.e., RGP cells first produce intermediate progenitor cells, which then divide further to produce neurons). How direct and indirect neurogenesis from RGP cells leads to the appropriate neocortical size and cell-type composition remains incompletely understood. In this study, we developed a combined retrovirus- and FlashTag-based labeling technique that allows clonal tracking of sequential RGP divisions and identification of progeny identities in vivo. Using this method, we show that divisions of mouse RGP cells giving rise to neurogenic (N), neurogenic intermediate progenitor (IP), and neurogenic proliferative intermediate progenitor (IPP) cells tend to generate similar numbers of pyramidal neurons. In the early neuronal progeny of RGP cells, the distribution of neurons produced by the N-, IP-, and IPP-producing divisions follows an "inside-out" pattern in the neocortex. Clonal analysis and mathematical modeling indicate that RGP cells initially give rise to neurons, IP, and IPP cells in a stochastic manner, followed by relatively stable transition patterns between direct and indirect neurogenesis across successive generations. These findings provide a comprehensive and novel understanding of the dynamics of cell division during cortical neurogenesis.The EMBO journalDirect and indirect neurogenesis from radial glial progenitor cell clones in the mouse neocortex.PMC127590822023YFF 12048022021ZD020250031725012820712592018SHZDZX012020CXJQ012019-0107-00-07-E00062319300442021ZD0200100Tong SYZhu YZhai ZYShen DLin YNLiu RHWang CXYu YCDeng HHLiu LYChen JYLi YXYang FWWang XYfalseDirect and indirect neurogenesis from radial glial progenitor cell clones in the mouse neocortex.The size and complexity of the neocortex are largely determined during brain development by neurogenesis from radial glial progenitor (RGP) cells. Neurogenesis from such cells can be direct (i.e., RGP cells give rise directly to neurons) or indirect (i.e., RGP cells first produce intermediate progenitor cells, which then divide further to produce neurons). How direct and indirect neurogenesis from RGP cells leads to the appropriate neocortical size and cell-type composition remains incompletely understood. In this study, we developed a combined retrovirus- and FlashTag-based labeling technique that allows clonal tracking of sequential RGP divisions and identification of progeny identities in vivo. Using this method, we show that divisions of mouse RGP cells giving rise to neurogenic (N), neurogenic intermediate progenitor (IP), and neurogenic proliferative intermediate progenitor (IPP) cells tend to generate similar numbers of pyramidal neurons. In the early neuronal progeny of RGP cells, the distribution of neurons produced by the N-, IP-, and IPP-producing divisions follows an "inside-out" pattern in the neocortex. Clonal analysis and mathematical modeling indicate that RGP cells initially give rise to neurons, IP, and IPP cells in a stochastic manner, followed by relatively stable transition patterns between direct and indirect neurogenesis across successive generations. These findings provide a comprehensive and novel understanding of the dynamics of cell division during cortical neurogenesis.2026-01-01T00:00:00Z2026 Jan2026-06-06T11:14:09.513Z2026-05-29T03:12:00.52ZS-EPMC127590824126665610.1038/s44318-025-00624-9