The Role of Activator E2Fs in Neural Stem Cell Activation and Exit from Quiescence

Abstract

Regenerative medicine offers tremendous potential for the treatment of irreversible damage to the brain. Activation of quiescent adult neural stem cells by clinical means to regenerate tissue can improve pathological outcomes of patients afflicted by brain trauma. Control of the cell- cycle is important in activating quiescent neural stem cells for the purpose of enhancing adult neurogenesis. Here, we uncover the role of cell-cycle regulatory transcription factors E2F1 and E2F3 in adult neural stem cell activation and characterize it. We hypothesize that the Retinoblastoma-E2F pathway is crucial for neural stem cell activation. We characterized the requirement of E2Fs1/3 for adult neural stem cells activation through a combination of multiple knockout timepoints in mice and novel markers used to identify distinct neural stem cell sub- populations. The results show a marked reduction in the neurogenic capacity of the adult brain, with common markers of proliferation and different progenitor-cell lineages decreased. Additionally, the ability of quiescent neural stem cells to transition to an active state is reduced. A whole genome-analysis of RNA isolated from E2Fs1/3-knockout adult neural stem cells has shown a shift from an active identity-state to a quiescent one. In the future, E2Fs1/3 could emerge as key regulators of quiescent stem cell activation, and thus could be potential targets for therapeutic control in order to enhance neurogenesis in patients with brain pathology.