Sox5 controls cell cycle progression in intermediate progenitor cells during dentate gyrus development.

The development of the dentate gyrus (DG) of the hippocampus is protracted over time in comparison with other brain regions such as hippocampal cornus ammoni or neocortex, extending over the first postnatal weeks. During DG postnatal development, neural stem cells (NSCs) will remain to generate the adult neurogenic niche that will sustain granule neuron (GN) production throughout life. NSCs in the DG divide to generate intermediate progenitor cells (IPCs), whose highly regulated dynamics of self-renewal or cell cycle exit decisions still remain poorly understood. Sox5 is a transcription factor (TF) essential for the establishment of adult NSCs, however, its potential role in Sox5 expressing IPCs during DG development remains unexplored. In this study, we demonstrate that conditional loss of Sox5 during embryonic development leads to critical alterations in cell proliferation and survival in IPCs. Specifically, following Sox5 loss, IPCs exhibit a shortening of S-phase duration in late postnatal and juvenile adult stages. Furthermore, these alterations in IPC cell cycle dynamics could be behind the defects in GN differentiation observed in Sox5-defective mice that ultimately leads to subtle morphological changes in DG architecture. Finally, we demonstrate that the additional loss of one Sox6 copy, a closely related TF to Sox5, lead to more profound disruptions in DG morphology than the one observed upon Sox5 loss. Overall, these findings point to a prominent role for Sox5 in combination with Sox6 in IPC cell cycle progression and GN maturation during postnatal DG development.