# Direct and indirect neurogenesis from radial glial progenitor cell clones in the mouse neocortex

## TL;DR

This study tracks how brain cells called radial glial progenitors generate neurons directly or indirectly during mouse brain development.

## Contribution

A novel retrovirus-FlashTag labeling method enables in vivo clonal tracking of RGP divisions and progeny identities.

## Key findings

- N, IP, and IPP cell divisions produce similar numbers of pyramidal neurons.
- Neurons from different division types show an 'inside-out' laminar distribution in the neocortex.
- RGP cells maintain stable transition probabilities between division types across generations.

## Abstract

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.

Radial glial progenitor (RGP) cells can give rise to neurons through different, direct or indirect, differentiation trajectories, but how this process ensures proper neocortical development remains incompletely understood. Using a novel labeling method to track RGP divisions and their cellular progeny in vivo, this study provides a more comprehensive understanding of the cell division dynamics during neocortical development in mice.

Clustering analysis identifies five distinct clonal types in the RGP-to-neuron differentiation pathway.Neurogenic (N), neurogenic intermediate progenitor (IP), and neurogenic proliferative intermediate progenitor (IPP) cell-producing divisions give rise to comparable numbers of pyramidal neurons.Neurons generated through N, IP, and IPP cell divisions exhibit a characteristic “inside-out” laminar distribution in the neocortex within the same developmental generation.RGP cells maintain stable transition probabilities among the three types of division patterns across generations.

Clustering analysis identifies five distinct clonal types in the RGP-to-neuron differentiation pathway.

Neurogenic (N), neurogenic intermediate progenitor (IP), and neurogenic proliferative intermediate progenitor (IPP) cell-producing divisions give rise to comparable numbers of pyramidal neurons.

Neurons generated through N, IP, and IPP cell divisions exhibit a characteristic “inside-out” laminar distribution in the neocortex within the same developmental generation.

RGP cells maintain stable transition probabilities among the three types of division patterns across generations.

Clonal tracking of sequential progenitor cell divisions and their progeny elucidates the differentiation patterns during neocortical development.