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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.


Organization of the C. elegans hermaphroditic gonadal arm. A mitotic zone (MZ) contains stem cells at the distal end, which ensure organ self-renewal as cells are consumed proximally for spermatogenesis (during larval development) or oogenesis and apoptosis (during adulthood). Differentiation of mitotic cells is controlled by opposing factors such as FBF-1/2 and GLD-1, expressed in opposing gradients. The cell cycle regulator cyclin E1 (CYE-1) is expressed throughout the MZ. Subregions are shown that are considered in cell cycle analysis: distal-most mitotic zone (DMMZ), medial mitotic zone (MMZ), and proximal mitotic zone (PMZ). Cell position can be measured by the number of rows to the distal end (rows 1 to 19 are numbered)
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Fig1: Organization of the C. elegans hermaphroditic gonadal arm. A mitotic zone (MZ) contains stem cells at the distal end, which ensure organ self-renewal as cells are consumed proximally for spermatogenesis (during larval development) or oogenesis and apoptosis (during adulthood). Differentiation of mitotic cells is controlled by opposing factors such as FBF-1/2 and GLD-1, expressed in opposing gradients. The cell cycle regulator cyclin E1 (CYE-1) is expressed throughout the MZ. Subregions are shown that are considered in cell cycle analysis: distal-most mitotic zone (DMMZ), medial mitotic zone (MMZ), and proximal mitotic zone (PMZ). Cell position can be measured by the number of rows to the distal end (rows 1 to 19 are numbered)

Mentions: The C. elegans germ line provides a stem-cell model system that is highly amenable to stem-cell cycle studies [18–21]. This germ line is contained in tube-like gonadal arms, with stem cells located at the distal end within a mitotic zone (MZ; Fig. 1). The stem cells ensure self-renewal throughout life, compensating for cell loss to spermatogenesis, which occurs during larval development, and oogenesis and apoptosis that occur during adulthood. The MZ contains cycling cells and expresses factors driving the cell cycle – such as the worm homologue of cyclin E, CYE-1 [22] – throughout the 20 cell rows that it spans. The MZ is patterned along its distal–proximal axis, notably by counteracting gradients of the Pumilio homologues FBF-1 and FBF-2, which promote the stem-cell fate [23, 24], and of factors such as GLD-1 that promote differentiation [25] (Fig. 1). These factors define steps of differentiation within the MZ, at rows ~6–8 and ~12 from the distal end [26], before the overt meiosis observed at row ~20. Cells do not undergo active migration from one zone to the other, but rather are displaced along the distal–proximal axis; their differentiation state progresses accordingly. The spatial layout of the MZ is important because it obviates the need for fine markers to assay differentiation states – distance to the distal end is a reliable differentiation marker – and because it makes it straightforward to assay the proliferative contribution to the tissue of all cell subpopulations. Although no spatial differences in cell cycle length were found in previous studies [27], variation in M-phase index hints at different cell cycle behavior along the distal–proximal axis [28].Fig. 1


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)

Organization of the C. elegans hermaphroditic gonadal arm. A mitotic zone (MZ) contains stem cells at the distal end, which ensure organ self-renewal as cells are consumed proximally for spermatogenesis (during larval development) or oogenesis and apoptosis (during adulthood). Differentiation of mitotic cells is controlled by opposing factors such as FBF-1/2 and GLD-1, expressed in opposing gradients. The cell cycle regulator cyclin E1 (CYE-1) is expressed throughout the MZ. Subregions are shown that are considered in cell cycle analysis: distal-most mitotic zone (DMMZ), medial mitotic zone (MMZ), and proximal mitotic zone (PMZ). Cell position can be measured by the number of rows to the distal end (rows 1 to 19 are numbered)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4538916&req=5

Fig1: Organization of the C. elegans hermaphroditic gonadal arm. A mitotic zone (MZ) contains stem cells at the distal end, which ensure organ self-renewal as cells are consumed proximally for spermatogenesis (during larval development) or oogenesis and apoptosis (during adulthood). Differentiation of mitotic cells is controlled by opposing factors such as FBF-1/2 and GLD-1, expressed in opposing gradients. The cell cycle regulator cyclin E1 (CYE-1) is expressed throughout the MZ. Subregions are shown that are considered in cell cycle analysis: distal-most mitotic zone (DMMZ), medial mitotic zone (MMZ), and proximal mitotic zone (PMZ). Cell position can be measured by the number of rows to the distal end (rows 1 to 19 are numbered)
Mentions: The C. elegans germ line provides a stem-cell model system that is highly amenable to stem-cell cycle studies [18–21]. This germ line is contained in tube-like gonadal arms, with stem cells located at the distal end within a mitotic zone (MZ; Fig. 1). The stem cells ensure self-renewal throughout life, compensating for cell loss to spermatogenesis, which occurs during larval development, and oogenesis and apoptosis that occur during adulthood. The MZ contains cycling cells and expresses factors driving the cell cycle – such as the worm homologue of cyclin E, CYE-1 [22] – throughout the 20 cell rows that it spans. The MZ is patterned along its distal–proximal axis, notably by counteracting gradients of the Pumilio homologues FBF-1 and FBF-2, which promote the stem-cell fate [23, 24], and of factors such as GLD-1 that promote differentiation [25] (Fig. 1). These factors define steps of differentiation within the MZ, at rows ~6–8 and ~12 from the distal end [26], before the overt meiosis observed at row ~20. Cells do not undergo active migration from one zone to the other, but rather are displaced along the distal–proximal axis; their differentiation state progresses accordingly. The spatial layout of the MZ is important because it obviates the need for fine markers to assay differentiation states – distance to the distal end is a reliable differentiation marker – and because it makes it straightforward to assay the proliferative contribution to the tissue of all cell subpopulations. Although no spatial differences in cell cycle length were found in previous studies [27], variation in M-phase index hints at different cell cycle behavior along the distal–proximal axis [28].Fig. 1

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.