Cdk4/CyclinD1 Overexpression in Neural Stem Cells Shortens G1, Delays Neurogenesis, and Promotes the Generation and Expansion of Basal Progenitors

Abstract

During mouse embryonic development, neural progenitors lengthen the G1 phase of the cell cycle and this has been suggested to be a cause, rather than a consequence, of neurogenesis. To investigate whether G1 lengthening alone may cause the switch of cortical progenitors from proliferation to neurogenesis, we manipulated the expression of cdk/cyclin complexes and found that cdk4/cyclinD1 overexpression prevents G1 lengthening without affecting cell growth, cleavage plane, or cell cycle synchrony with interkinetic nuclear migration. Specifically, overexpression of cdk4/cyclinD1 inhibited neurogenesis while increasing the generation and expansion of basal (intermediate) progenitors, resulting in a thicker subventricular zone and larger surface area of the postnatal cortex originating from cdk4/cyclinD1-transfected progenitors. Conversely, lengthening of G1 by cdk4/cyclinD1-RNAi displayed the opposite effects. Thus, G1 lengthening is necessary and sufficient to switch neural progenitors to neurogenesis, and overexpression of cdk4/cyclinD1 can be used to increase progenitor expansion and, perhaps, cortical surface area.

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

“…5). These results are also consistent with the longer G1 observed in rapamycin-treated neural stem cells Alterations in the precise length of G1 phase in stem cells have been correlated with defects in differentiation (Lange et al 2009;Li et al 2012). In summary, our in vitro results indicate that rapamycin inhibits neural progenitor proliferation and differentiation.…”

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…Recently, Lange et al [40] demonstrated that forcing the lengthening of G 1 is sufficient to promote the exit of the cell cycle of cortical progenitors and their differentiation into projection neurons. As our data support an increased rate of precursor cell cycle exit in Cdk6 À/À neurogenic regions, we compared the length of G 1 in Cdk6-knockout and WT animals.…”

“…As our data support an increased rate of precursor cell cycle exit in Cdk6 À/À neurogenic regions, we compared the length of G 1 in Cdk6-knockout and WT animals. To this aim, we performed cumulative S-phase labeling with BrdU [18,40] (Fig. 6A-6D).…”

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…By impairing stem cell division even mildly, the proportion of symmetric divisions is concomitantly reduced, depleting the progenitor pool and limiting the total number of neurons that can be generated (Thornton & Woods, 2009; Alcantara & O'Driscoll, 2014). On the other hand, altering the cell cycle length, in particular the G1 phase, contributes to switching of neural progenitors from proliferative to differentiating states (Calegari et al , 2005; Lange et al , 2009; Li et al , 2011). …”