Dynamic Control of Adult Neural Stem Cells

There are some neural stem cells in two restricted regions of theadult brain: the subventricular zone of the lateral ventricles andthe subgranular zone of the hippocampal dentate gyrus. Unlikeembryonic neural stem cells, these adult neural stem cells aremostly dormant/quiescent, and they only occasionally proliferateand give rise to new neurons. The molecular basis for thedifference between embryonic and adult neural stem cells is notwell understood. We found that embryonic neural stem cells expressHes۱/Hes۵ and proneural genes in an oscillatory manner.When their oscillatory expression is dampened, proliferation ofneural stem cells is impaired, resulting in microcephaly, indicatingthat oscillatory expression of Hes۱/Hes۵ and proneuralgenes is very important for efficient proliferation of neural stemcells. To investigate the expression dynamics and functions ofHes and proneural genes in adult neural stem cells, we performedlive-imaging and loss-of-function and gain-of-functionanalyses. We found that in the adult brain, Hes۱ expression ishigh and sustained, while Ascl۱ expression is negative. Furthermore,induction of sustained Hes۱ expression can inhibitproliferation of embryonic neural stem cells and is sufficient toblock neurogenesis and maintain quiescent neural stem cells inthe adult brain. By contrast, inactivation of Hes genes inducesAscl۱ expression and activates neurogenesis in the adult brain.These results indicate that sustained Hes۱ expression and resultantrepression of Ascl۱ may lead to the quiescent state of adultneural stem cells. Thus, Ascl۱ oscillations may be important foractivation of adult neural stem cells, suggesting that optogeneticinduction of Ascl۱ oscillations may be one of the strategies toactivate endogenous neurogenesis in the adult brain.