FIGURE 5

FIGURE 5

Schematic of the cell cycle including the most important information about the decision to enter quiescence, remain in cycle or differentiate. (A) General cell cycle knowledge, illustrating phases G1, S, G2, and M and the most important checkpoints (purple). During the cell cycle, proteins involved in transcription, translation, DNA replication and DNA repair are upregulated. The schematic includes proliferation markers MCM, PCNA, and Ki67 (gray) that are expressed in different phases of the cell cycle and commonly used to define proliferating NSCs. During the cell cycle, cells can enter into the quiescence state in G1, the decisions for entry happening at a R-point in G1. After passing the R-point, cells are committed to fulfill another cell cycle. Another important check-point is the bifurcation point right after mitosis, a window in which cells are sensitive to mitogen signals that influence CDK2 (R1 and R2 window on the schematic). Cells with a normal level of CDK2 will keep cycling, whereas cells with low levels of CDK2 will enter a transient quiescence and will face a second restriction window at the end of G1, controlled by the CDK inhibitor p21. Only cells that built up enough CDK will be able to bypass quiescence and eventually re-enter quiescence. (B) NSC-specific quiescence cycle. Quiescence can be entered in G1, or G2 (this remains to be shown for vertebrates). During quiescence, genes involved in cell-cell communication, cell adhesion and cell signaling are upregulated, stressing that quiescence is an actively maintained state. Some data (e.g., the dynamics of miR-9 expression) suggest that quiescence can be seen as a cycle, but alternative models exist. Quiescent cells express p21, p27, p57, and p130. Quiescence is heterogeneous, and deeper and shallower sub-states exist. miR-9 is nuclear in deeply quiescent cells. Some NSCs that are insensitive to Notch blockade can also be interpreted as deeply quiescent. A “pro-activated” state precedes activation proper. In this state, NSCs express ascl1, which will also be maintained during activation and differentiation (Pardee, 1974; Alunni et al., 2013; Spencer et al., 2013; Andersen et al., 2014; Katz et al., 2016).