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Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation.

Chiang M, Cinquin A, Paz A, Meeds E, Price CA, Welling M, Cinquin O - BMC Biol. (2015)

Bottom Line: Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached.Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental & Cell Biology, University of California, Irvine, California, USA.

ABSTRACT

Background: Stem cells are thought to play a critical role in minimizing the accumulation of mutations, but it is not clear which strategies they follow to fulfill that performance objective. Slow cycling of stem cells provides a simple strategy that can minimize cell pedigree depth and thereby minimize the accumulation of replication-dependent mutations. Although the power of this strategy was recognized early on, a quantitative assessment of whether and how it is employed by biological systems is missing.

Results: Here we address this problem using a simple self-renewing organ - the C. elegans gonad - whose overall organization is shared with many self-renewing organs. Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached. This compromise is such that worm germ-line stem cells should cycle more slowly than their differentiating counterparts, but only by a modest amount. Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.

Conclusions: Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

No MeSH data available.


Cyclin E levels are graded across the DMMZ and MMZ, and are differentially dependent on cell cycle phase in the DMMZ and MMZ. a Example of CYE-1 staining pattern in a gonadal arm at L4 + 1 day (color-coded using ImageJ’s “Fire” lookup table). CYE-1 levels appear to start low in the distal region, rise, and then fall in the proximal region. b Quantification of nuclear CYE-1 levels using 7508 cells segmented from 30 gonadal arms. Each dot represents a cell; the red line is the average at each cell row, with a 95 % bootstrapped confidence interval. c, d Cells with typical G1 morphology (arrows in c) have higher CYE-1 content than their neighbors (d; arrows point to same G1 cells as in c). e Scatterplot of nuclear CYE-1 content vs. DNA content, showing that cells with lower DNA content – i.e. early in the cell cycle – have moderately higher levels of CYE-1 than cells with higher DNA content. Density colored via “jet” lookup table (red: high density, blue: low density), and piecewise-linear trend line computed as described in “Methods”. f, g Variation of CYE-1 content with cell cycle phase is lesser for cells in the DMMZ (f; virtually flat trend line) than in the MMZ (g; steeper trend line). The difference between DMMZ and MMZ is statistically significant (95 % bootstrapped CI for difference in slopes of first component of trend lines: 0.024–0.38, n = 50,000 replicates). Arrows show two clusters at low and high DNA content. h, i Quantification of nuclear CYE-1 profile as in (a), but considering only cells with low (h) or high (i) DNA content
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Fig5: Cyclin E levels are graded across the DMMZ and MMZ, and are differentially dependent on cell cycle phase in the DMMZ and MMZ. a Example of CYE-1 staining pattern in a gonadal arm at L4 + 1 day (color-coded using ImageJ’s “Fire” lookup table). CYE-1 levels appear to start low in the distal region, rise, and then fall in the proximal region. b Quantification of nuclear CYE-1 levels using 7508 cells segmented from 30 gonadal arms. Each dot represents a cell; the red line is the average at each cell row, with a 95 % bootstrapped confidence interval. c, d Cells with typical G1 morphology (arrows in c) have higher CYE-1 content than their neighbors (d; arrows point to same G1 cells as in c). e Scatterplot of nuclear CYE-1 content vs. DNA content, showing that cells with lower DNA content – i.e. early in the cell cycle – have moderately higher levels of CYE-1 than cells with higher DNA content. Density colored via “jet” lookup table (red: high density, blue: low density), and piecewise-linear trend line computed as described in “Methods”. f, g Variation of CYE-1 content with cell cycle phase is lesser for cells in the DMMZ (f; virtually flat trend line) than in the MMZ (g; steeper trend line). The difference between DMMZ and MMZ is statistically significant (95 % bootstrapped CI for difference in slopes of first component of trend lines: 0.024–0.38, n = 50,000 replicates). Arrows show two clusters at low and high DNA content. h, i Quantification of nuclear CYE-1 profile as in (a), but considering only cells with low (h) or high (i) DNA content

Mentions: To begin identifying mechanisms potentially responsible for slower stem-cell cycling in the C. elegans germ line, we quantified the spatial expression profile of the cell cycle regulator CYE-1. We focused on this regulator because it is expressed in the MZ and is required for germ-cell cycling [22, 47] and because of its intriguing regulation: it is repressed by the proximal, differentiation-promoting factor GLD-1 [48, 49], but its transcript is also bound by the repressor FBF-1 [50], which acts to promote stem-cell fate distally. Nuclear CYE-1 expression follows a biphasic gradient within the MZ, with a peak at row 9 (Fig. 5a, b). A gradient of CYE-1 thus spans the region comprising rows 1–11, in which we showed that a cell cycle gradient exists. The difference between the DMMZ and MMZ is modest (11 %) but statistically significant (p < 1.0 × 10–14; Wilcoxon rank sum test). Average nuclear CYE-1 levels thus correlate positively with cell cycle speed.


Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation.

Chiang M, Cinquin A, Paz A, Meeds E, Price CA, Welling M, Cinquin O - BMC Biol. (2015)

Cyclin E levels are graded across the DMMZ and MMZ, and are differentially dependent on cell cycle phase in the DMMZ and MMZ. a Example of CYE-1 staining pattern in a gonadal arm at L4 + 1 day (color-coded using ImageJ’s “Fire” lookup table). CYE-1 levels appear to start low in the distal region, rise, and then fall in the proximal region. b Quantification of nuclear CYE-1 levels using 7508 cells segmented from 30 gonadal arms. Each dot represents a cell; the red line is the average at each cell row, with a 95 % bootstrapped confidence interval. c, d Cells with typical G1 morphology (arrows in c) have higher CYE-1 content than their neighbors (d; arrows point to same G1 cells as in c). e Scatterplot of nuclear CYE-1 content vs. DNA content, showing that cells with lower DNA content – i.e. early in the cell cycle – have moderately higher levels of CYE-1 than cells with higher DNA content. Density colored via “jet” lookup table (red: high density, blue: low density), and piecewise-linear trend line computed as described in “Methods”. f, g Variation of CYE-1 content with cell cycle phase is lesser for cells in the DMMZ (f; virtually flat trend line) than in the MMZ (g; steeper trend line). The difference between DMMZ and MMZ is statistically significant (95 % bootstrapped CI for difference in slopes of first component of trend lines: 0.024–0.38, n = 50,000 replicates). Arrows show two clusters at low and high DNA content. h, i Quantification of nuclear CYE-1 profile as in (a), but considering only cells with low (h) or high (i) DNA content
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Related In: Results  -  Collection

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Fig5: Cyclin E levels are graded across the DMMZ and MMZ, and are differentially dependent on cell cycle phase in the DMMZ and MMZ. a Example of CYE-1 staining pattern in a gonadal arm at L4 + 1 day (color-coded using ImageJ’s “Fire” lookup table). CYE-1 levels appear to start low in the distal region, rise, and then fall in the proximal region. b Quantification of nuclear CYE-1 levels using 7508 cells segmented from 30 gonadal arms. Each dot represents a cell; the red line is the average at each cell row, with a 95 % bootstrapped confidence interval. c, d Cells with typical G1 morphology (arrows in c) have higher CYE-1 content than their neighbors (d; arrows point to same G1 cells as in c). e Scatterplot of nuclear CYE-1 content vs. DNA content, showing that cells with lower DNA content – i.e. early in the cell cycle – have moderately higher levels of CYE-1 than cells with higher DNA content. Density colored via “jet” lookup table (red: high density, blue: low density), and piecewise-linear trend line computed as described in “Methods”. f, g Variation of CYE-1 content with cell cycle phase is lesser for cells in the DMMZ (f; virtually flat trend line) than in the MMZ (g; steeper trend line). The difference between DMMZ and MMZ is statistically significant (95 % bootstrapped CI for difference in slopes of first component of trend lines: 0.024–0.38, n = 50,000 replicates). Arrows show two clusters at low and high DNA content. h, i Quantification of nuclear CYE-1 profile as in (a), but considering only cells with low (h) or high (i) DNA content
Mentions: To begin identifying mechanisms potentially responsible for slower stem-cell cycling in the C. elegans germ line, we quantified the spatial expression profile of the cell cycle regulator CYE-1. We focused on this regulator because it is expressed in the MZ and is required for germ-cell cycling [22, 47] and because of its intriguing regulation: it is repressed by the proximal, differentiation-promoting factor GLD-1 [48, 49], but its transcript is also bound by the repressor FBF-1 [50], which acts to promote stem-cell fate distally. Nuclear CYE-1 expression follows a biphasic gradient within the MZ, with a peak at row 9 (Fig. 5a, b). A gradient of CYE-1 thus spans the region comprising rows 1–11, in which we showed that a cell cycle gradient exists. The difference between the DMMZ and MMZ is modest (11 %) but statistically significant (p < 1.0 × 10–14; Wilcoxon rank sum test). Average nuclear CYE-1 levels thus correlate positively with cell cycle speed.

Bottom Line: Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached.Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

View Article: PubMed Central - PubMed

Affiliation: Department of Developmental & Cell Biology, University of California, Irvine, California, USA.

ABSTRACT

Background: Stem cells are thought to play a critical role in minimizing the accumulation of mutations, but it is not clear which strategies they follow to fulfill that performance objective. Slow cycling of stem cells provides a simple strategy that can minimize cell pedigree depth and thereby minimize the accumulation of replication-dependent mutations. Although the power of this strategy was recognized early on, a quantitative assessment of whether and how it is employed by biological systems is missing.

Results: Here we address this problem using a simple self-renewing organ - the C. elegans gonad - whose overall organization is shared with many self-renewing organs. Computational simulations of mutation accumulation characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem cells allow for an advantageous compromise to be reached. This compromise is such that worm germ-line stem cells should cycle more slowly than their differentiating counterparts, but only by a modest amount. Experimental measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.

Conclusions: Our findings shed light both on design principles that underlie the role of stem cells in delaying aging and on evolutionary forces that shape stem-cell gene regulatory networks.

No MeSH data available.