Dynamic Control of Embryonic Neural Stem Cells

During brain development, neural stem cells proliferate intensivelywhile they change their competency over time, givingrise to various types of neurons and glial cells sequentially. Itis therefore very important to maintain neural stem cells untilthe final stage of development to generate a sufficient numberof cells and a full diversity of cell types. To understand themechanism of maintenance of embryonic neural stem cells, weinvestigated the expression dynamics and functions of Hes andproneural genes. We found that the Notch effector genes Hes۱and Hes۵ are expressed by neural stem cells, and that in theabsence of Hes۱ and Hes۵, proneural genes such as Ascl۱ andMath۳ are up-regulated, accelerating neuronal differentiationand exhausting neural stem cells prematurely. By contrast, inthe absence of Ascl۱۱ and Math۳, many neurons were missingand, instead, those cells that normally differentiate intoneurons adopted the astroglial fate. Thus, proneural genes likeAscl۱ and Math۳ direct neuronal versus glial fate determination.These results indicate that antagonistic regulation betweenNotch effectors and proneural genes regulate neural stem cellproliferation, neurogenesis and gliogenesis in the developingbrain. In the absence of Hes or proneural genes, the proliferationof neural stem cells was impaired in the developing nervoussystem, suggesting that both Hes and proneural genes alsoplay an important role in proliferation of neural stem cells.We next found that both Hes۱ and Hes۵ are expressed in an oscillatorymanner by embryonic neural stem cells, and that Hes۱/Hes۵ oscillations drive cyclic expression of proneural genes.During neuronal differentiation, Hes۱/Hes۵ expression disappearsand proneural gene expression becomes sustained, whileHes۱/Hes۵ expression becomes dominant during astroglial differentiation.Furthermore, optogenetic induction of Ascl۱ oscillationactivates proliferation of neural stem cells, whereassustained expression of Ascl۱ induces neuronal differentiation.Thus, oscillatory versus sustained expression of these factorsmay be important for their activities. These results also suggest that the multipotent undifferentiated state is controlled bymultiple oscillating fate-determination factors, while the fatechoice is controlled by sustained expression of a selected fatedeterminationfactor.