Selective Lengthening of the Cell Cycle in the Neurogenic Subpopulation of Neural Progenitor Cells during Mouse Brain Development

Abstract

During embryonic development of the mammalian brain, the average cell-cycle length of progenitor cells in the ventricular zone is known to increase. However, for any given region of the developing cortex and stage of neurogenesis, the length of the cell cycle is thought to be similar in the two coexisting subpopulations of progenitors [i.e., those undergoing (symmetric) proliferative divisions and those undergoing (either asymmetric or symmetric) neuron-generating divisions]. Using cumulative bromodeoxyuridine labeling of Tis21-green fluorescent protein knock-in mouse embryos, in which these two subpopulations of progenitors can be distinguished in vivo, we now show that at the onset as well as advanced stages of telencephalic neurogenesis, progenitors undergoing neuron-generating divisions are characterized by a significantly longer cell cycle than progenitors undergoing proliferative divisions. In addition, we find that the recently characterized neuronal progenitors dividing at the basal side of the ventricular zone and in the subventricular zone have a longer G 2 phase than those dividing at the ventricular surface. These findings are consistent with the hypothesis (Calegari and Huttner, 2003) that cell-cycle lengthening can causally contribute to neural progenitors switching from proliferative to neuron-generating divisions and may have important implications for the expansion of somatic stem cells in general.

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

“…Interestingly, we found that the Tubb3-positive midbodies are ∼ 5% at E12.5 and 430% at E14.5 ( Figures 3c and d), an increase well correlated with the increase of neurogenic divisions that takes place between the two stages. 40 The above data show that the expression of Tubb3 in proliferating cortical progenitors, at levels lower than in differentiating neurons but still clearly detectable, is much more widespread than previously believed and suggest that the incorporation of Tubb3 in midbody microtubules could be one of the factors that render neurogenic divisions sensitive to CIT-K inactivation. To functionally test this hypothesis we resorted to HeLa cells in which we increased (Supplementary Figures S2B and C) or decreased (Supplementary Figure S2D) the levels of TUBB3, concomitantly with CIT-K knockdown.…”

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…After sufficient NPCs expansion, neurogenesis then begins, which requires switching of the cleavage plane from horizontal to vertical (Rakic, 1995; Lancaster et al , 2013). The defect in apical progenitor expansion at the ventricular zone via vertical orientation accompanied by premature neurogenesis has been shown to occur due to cell cycle delay (Calegari et al , 2005; Tapias et al , 2014). …”

“…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). …”

S‐phase duration is the main target of cell cycle regulation in neural progenitors of developing ferret neocortex

“…Studies in mouse have shown that cell cycle duration increases throughout the proliferative areas along neurogenesis, correlating with the loss of the self‐renewing capacity of neural progenitors and the concomitant increase in their neurogenic output (Calegari et al, 2005; Caviness and Takahashi, 1995; Takahashi et al, 1995). This cell cycle lengthening reflects an increase in bIP abundance, as it is mainly due to the lengthening of G1‐phase in the transition from APs to bIPs (Arai et al, 2011; Calegari et al, 2005).…”

“…This cell cycle lengthening reflects an increase in bIP abundance, as it is mainly due to the lengthening of G1‐phase in the transition from APs to bIPs (Arai et al, 2011; Calegari et al, 2005). The importance of the G1‐phase in the switch from proliferation to differentiation was supported by experimental manipulations in which artificial lengthening of this phase was shown to cause premature neurogenesis (Calegari and Huttner, 2003), whereas its shortening had the opposite effect, leading to an expansion of the progenitor pool (Lange et al, 2009; Pilaz et al, 2009).…”