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Comparative Study
. 2005 Jul 13;25(28):6533-8.
doi: 10.1523/JNEUROSCI.0778-05.2005.

Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development

Federico Calegari  1 , Wulf Haubensak, Christiane Haffner, Wieland B Huttner
Affiliations
Comparative Study

Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development

Federico Calegari et al. J Neurosci. .

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.

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Figures

Figure 1.
Figure 1.
Cumulative BrdU labeling of NE/RG cells in E10.5 and E14.5 heterozygous Tis21-GFP embryos. A, C-C″, Cells in the telencephalic neuroepithelium of an E10.5 (A) and E14.5 (C-C″) heterozygous Tis21-GFP embryo stained for DNA (white; A, C) and immunostained for GFP (green; A, C′) and BrdU (4 h labeling; red; A, C″). Note the examples of the four types of stained nuclei, (1) GFP-/BrdU- (white arrowheads), (2) GFP+/BrdU- (green arrowheads), (3) GFP-/BrdU+ (red arrowheads), and (4) GFP+/BrdU+ (green/red arrowheads), in the merged image (A) and the three individual channels (C-C″). Solid and dashed lines represent the basal boundary of VZ to the neuronal layer (NL) (A) and SVZ (C-C″) and the apical (ap) surface, respectively. B, D, Cumulative BrdU labeling of GFP- (filled circles) and GFP+ (open squares) nuclei, identified as in A and C-C″, in VZ cells at E10.5 (B) and E14.5 (D); all nuclei stained had a BrdU labeling index 1.0. Data are the mean of three (E14.5; 12 h; 2 litters) independent litters; bars indicate SD (E14.5; 12 h; variation of the 2 litters from the mean). Horizontal dashed lines represent the growth fraction.
Figure 2.
Figure 2.
BrdU labeling in mitotic neuronal progenitors. Dashed lines indicate mitotic basal (a-e) and apical (g-k) progenitors in the telencephalic SVZ (basal) and VZ (apical), respectively, of an E14.5 Tis21-GFP heterozygous embryo exposed to BrdU for 4 h. Mitotic cells were identified by DAPI (a, g; blue) and anti-phosphohistone H3 (PH3; b, h; white) staining. Only GFP+ (c, i; green) mitotic progenitors were analyzed for incorporation of BrdU (d, j; red). White arrowheads at the margins of g-k indicate the apical surface of the VZ. f, l, Percentage of BrdU- (black bars) and BrdU+ (red bars) mitotic GFP+ basal (f) and apical (l) neuronal progenitors [5 embryos from 3 litters; basal progenitors, n = 21; apical progenitors, n = 33; each randomly distributed into 3 groups for SD (bars); basal BrdU+ percentage vs apical BrdU+ percentage; p < 0.05].
Figure 3.
Figure 3.
Relationship between interkinetic nuclear migration, Tis21-GFP expression, and BrdU incorporation of NE/RG cells and basal/SVZ progenitors. White nuclei, GFP- NE cells undergoing proliferative divisions; dark gray nuclei, GFP+ NE/RG cells and basal/SVZ progenitors undergoing neurogenic divisions; hatched boxes, S phase nuclei incorporating BrdU; dark gray polygons, neurons. Lines flanked by arrows indicate the length of TC - TS (the total length of the cell cycle minus the S phase) for GFP- versus GFP+ NE/RG cells and of TG2 +M (the G2 phase plus the minimum period at the end of the S phase necessary to incorporate detectable amounts of BrdU plus the fraction of M phase needed to identify condensed chromatids or detect anti-phosphohistone H3 immunoreactivity) for GFP+ NE/RG cells versus GFP+ basal/SVZ progenitors. The slope of the apical-to-basal migration of nuclei indicates the difference in the length of G1. For details, see text and supplemental material (available at www.jneurosci.org).
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