Direct 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.