Online Brain Science Seminar Series (BSS)
Online Brain Science Seminar Series(Online BSS)
Dr. Ryoichiro Kageyama
Monday, November 30th 2020, 16:00-17:30
Dynamic transcriptional control of neural stem cells
During brain development, neural stem cells (NSCs) proliferate intensively while they change their competency over time, giving rise to various types of neurons and glial cells sequentially. It is therefore very important to maintain NSCs until the final stage of development to generate a sufficient number of cells and a full diversity of cell types. We found that the proneural factor Ascl1, the astrogenic factor Hes1, and the oligodendrogenic factor Olig2 are expressed in an oscillatory manner in NSCs but exhibit sustained expression during differentiation into neurons, astrocytes, and oligodendrocytes, respectively. Hes1 expression autonomously oscillates by negative feedback in NSCs, and Hes1 oscillations periodically repress other factors, thereby driving their oscillations. Optogenetic analysis demonstrated that Ascl1 induces neuronal differentiation when its expression is sustained but activates proliferation of NSCs when its expression is oscillatory. These results indicated that same factors exhibit opposing functions depending on their expression patterns. The expression of the Notch ligand Delta-like1 (Dll1), which is controlled by Hes1, is also oscillatory in NSCs, but when Dll1 expression is accelerated or delayed, Dll1 oscillations are dampened. Under this condition, Hes1 oscillations are also dampened, and proliferation of NSCs is impaired, which causes microcephaly. These results suggest that oscillatory expression is important for proliferation of active NSCs in the embryonic brain. By contrast, NSCs in the adult brain are mostly quiescent. In these cells, Hes1 is expressed at high levels and continuously represses Ascl1 expression. Furthermore, induction of sustained Hes1 expression is sufficient to maintain the quiescence, while Ascl1 oscillation can activate NSCs and neurogenesis in the adult brain. These results suggest that oscillatory versus sustained transcriptional control regulates active versus quiescent NSCs.