Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity.

The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome (a genetic disorder known to accelerate aging), rejuvenated aged hippocampal NSCs, which already lost proliferative and neurogenic potential. Such rejuvenated NSCs proliferated and produced new neurons continuously at the level observed in juvenile hippocampi, leading to improved cognition. Epigenome, transcriptome, and live-imaging analyses indicated that this gene combination induces up-regulation of embryo-associated genes and down-regulation of age-associated genes by changing their chromatin accessibility, thereby rejuvenating aged dormant NSCs to function like juvenile active NSCs. Thus, aging of NSCs can be reversed to induce functional neurogenesis continuously, offering a way to treat age-related neurological disorders.

Transcriptional control of neural stem cell activity.

In the adult brain, neural stem cells (NSCs) are under the control of various molecular mechanisms to produce an appropriate number of neurons that are essential for specific brain functions. Usually, the majority of adult NSCs stay in a non-proliferative and undifferentiated state known as quiescence, occasionally transitioning to an active state to produce newborn neurons. This transition between the quiescent and active states is crucial for the activity of NSCs. Another significant state of adult NSCs is senescence, in which quiescent cells become more dormant and less reactive, ceasing the production of newborn neurons. Although many genes involved in the regulation of NSCs have been identified using genetic manipulation and omics analyses, the entire regulatory network is complicated and ambiguous. In this review, we focus on transcription factors, whose importance has been elucidated in NSCs by knockout or overexpression studies. We mainly discuss the transcription factors with roles in the active, quiescent, and rejuvenation states of adult NSCs.

Hes1 oscillation frequency correlates with activation of neural stem cells.

Quiescent neural stem cells (NSCs) are occasionally activated to undergo proliferation and subsequent neuronal differentiation. It was previously shown that the transcriptional repressor Hes1 is involved in both active and quiescent states of NSCs: when Hes1 expression oscillates, it periodically represses the proneural gene Ascl1, thereby driving Ascl1 oscillations, which regulate the active state, while sustained Hes1 expression continuously suppresses Ascl1, promoting quiescence. However, it remains to be analyzed how the transition from quiescent to active states of NSCs is controlled. Here, we found that overexpression of the active form of Notch1 significantly activates NSCs in both in-vitro and in-vivo conditions and that its levels are proportional to NSC activation. The active form of Notch1 induces a burst of Hes1 oscillations in quiescent NSCs, and the frequency of Hes1 oscillations, rather than the Hes1 peak levels, correlates with the efficiency of NSC activation. These results raised the possibility that bursting Hes1 oscillations could increase the chance of Ascl1 oscillations in quiescent NSCs, suggesting that Notch1-induced Hes1 oscillation is a cue for a transition from quiescent to active states of NSCs.