It is well understood that cell-cycle progression regulates many cellular processes beyond those required for cell division. For instance, CYCLIN-D1 has been previously described to induce an IPC state in the cortex17,18 and promote neurogenesis in the spinal cord19, which is consistent with our bioinformatic and functional experiments. In contrast, experiments on human embryonic stem cell (hESC) differentiation have shown that perturbing progression of S- and G2-phases promotes pluripotency maintenance. These authors found that the link between stem cell maintenance and specific cell-cycle phases was due to the stabilisation of p53 and activation of the TGFß pathway during S-phase perturbation, and upregulation of CYCLIN-B1 when G2 was delayed20. Analogous to our findings, they demonstrated that knockdown of CCNB1 led to the suppression of pluripotency markers, while overexpression of CYCLIN-B1 maintained hESCs in a pluripotent state20. Hence, the functional link between CYCLIN-B1 and the maintenance of stem cell features is conserved between mouse RGCs and hESCs, which suggests that this may be a widely exploited relationship in diverse stem cell populations.
Summary
We reveal that, while CYCLIN-D1 promotes the commitment of progenitors to cortical neurogenesis, CYCLIN-B1/2 and CDK1 maintain RGCs in an undifferentiated state by activating NOTCH signalling.
One of the mechanisms by which asymmetric divisions result in commitment to neuronal differentiation is via the unequal inheritance of cell-fate determinants between daughter cells. For instance, RGC daughter cells that inherit high levels of active NOTCH signalling components tend to remain as RGCs, while those with lower levels of NOTCH pathway activity commit to neurogenesis7,9,10,11. Gain- and loss-of-function studies have also demonstrated the transcription factor SOX2 to have key functions in regulating stem cell maintenance12,13. Consistent with this, SOX2 is asymmetrically inherited during cortical progenitor division, such that it is expressed at higher levels in RGCs compared with IPCs.
