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Developmental cell biology

C. elegans cell cycles: invariance and stem cell divisions

Key Points

  • The somatic lineage of the hermaphroditic nematode Caenorhabditis elegans has been mapped and is largely invariant, whereas germ cells proliferate continuously in a stem cell niche during larval and adult stages.

  • Early embryonic cell divisions are rapid and lack G1 (gap 1) and G2 (gap 2) phases. The introduction of a G2 phase is first observed at gastrulation, and the available evidence indicates that G1 phase is only present late in embryogenesis in a small minority of actively dividing cells.

  • Variations in early embryonic cell-cycle timing between lineages are due to different rates of DNA replication, which are attributable, in part, to the differential activation of the DNA-replication checkpoint.

  • Post-embryonic cell lineages are tightly regulated, with rounds of cell divisions beginning and ending at specific points during larval development. The extrinsic or intrinsic signals that determine the timing of initial cell-cycle entry are not known, although alterations in the heterochronic pathway, which specifies the order of larval programmes, can indirectly alter the timing of cell divisions.

  • The effectors of cell-cycle entry and exit are conserved cell-cycle regulators and include: G1 cyclin–CDK complexes, which are required for cell-cycle entry; and a CDK inhibitor, an Rb homologue and an SCF ubiquitin ligase complex, which mediate cell-cycle exit.

  • Cell-cycle perturbations usually do not block differentiation, although the failure to produce adequate cell numbers can alter differentiation choices.

  • Endoreplication (which is a cell cycle that lacks mitosis) occurs in the intestine and hypodermis, and is apparently used to increase the genome ploidy without the disruption of organ structure that would occur as a result of mitotic division.

  • Germ cell proliferation is dependent on the Delta homologue LAG-2 signal that is provided by the distal tip cell and is recognized by the GLP-1/Notch receptor on germ cells. In the absence of GLP-1 signalling, germ cells enter meiosis. In L3/L4 larval-stage hermaphrodites, proximal germ cells, which lack the LAG-2 signal, enter meiosis to create sperm, whereas in adults, germ cells enter meiosis to generate oocytes.

  • GLP-1 signalling maintains mitotic proliferation of germ cells by inhibiting a translational inhibitor (GLD-1) and a cytoplasmic poly(A) polymerase complex (GLD-2–GLD-3) that function in parallel pathways. GLD-1 and GLD-3 expression is inhibited in proliferating germ cells by translational repression through the PUF family members FBF-1 and FBF-2.

  • Cell-cycle regulators that mediate cell-cycle exit in somatic cells are not required for the negative regulation of germ cell proliferation, except in cases in which germ cell proliferation is halted in response to extrinsic signals (for example, lack of food).

Abstract

The adult Caenorhabditis elegans nematode, a small roundworm, has a precisely defined number of somatic cells that create organs that are also found in larger animals, including intestine, muscles, skin, an excretory system and a primitive brain. Every cell has a defined role in this sophisticated, but tiny animal. Therefore, stringent control of the cell cycle is required to produce the almost invariant cell lineage that generates the C. elegans somatic body plan. The proliferation of germ cells is regulated differently, and occurs within a stem cell niche.

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Figure 1: The C. elegans hermaphrodite cell lineage.
Figure 2: Early embryonic lineage and founder cells.
Figure 3: Heterochronic effects on cell lineage.
Figure 4: Proposed models for the regulation of cell-cycle entry and cell-cycle exit.
Figure 5: Endoreplication in the intestine.
Figure 6: Vulval cell fate decisions are linked to the cell cycle.
Figure 7: The gonad of an adult hermaphrodite and the regulation of meiotic entry.

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Acknowledgements

I thank T. Schedl, D. Hansen, J. Gaertig and members of the Kipreos laboratory for critical reading of the manuscript, and B. Goldstein for the use of movie frames of a moving adult Caenorhabditis elegans that were used to create the image in Figure 1. Research in the Kipreos laboratory is supported by grants from the National Institutes of Health and the American Cancer Society.

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DATABASES

Swiss-Prot

CDK2

CDK4

Wormbase

CDC-25.1

cdk-4

cki-1

cki-2

cul-1

cul-2

cyd-1

cye-1

DBL-1

DPL-1

efl-1

EFL-2

fbf-1

fbf-2

gld-1

gld-2

gld-3

glp-1

K03E5.3

lag-2

lin-12

lin-14

lin-23

lin-28

lin-35

nos-1

nos-2

PIE-1

SKR-1

SKR-2

WEE-1.3

FURTHER INFORMATION

Edward Kipreos' laboratory

Glossary

DNA-REPLICATION CHECKPOINT

This cell-cycle checkpoint ensures that mitosis is not initiated when DNA replication is either blocked or ongoing.

BLAST CELL

A cell that has not undergone terminal differentiation and that divides to produce cells of a committed cell lineage.

SYNCYTIUM

A common (shared) cytoplasm containing more than one nucleus.

G0 PHASE

A 'resting' (quiescent) cell-cycle stage, in which a cell does not progress through the cell cycle. Cells enter G0 phase from G1 phase, and after receiving the proper stimulus they can return to G1 phase and continue cell-cycle progression.

HETEROCHRONIC GENE

A gene that regulates the timing of developmental events. Mutations in heterochronic genes affect the timing of developmental programmes without overtly altering the programmes themselves.

FOUNDER CELL

A C. elegans early embryonic blast cell, the descendants of which divide relatively synchronously and produce a defined subset of tissue types.

CYCLIN-DEPENDENT KINASE

(CDK). A protein kinase that requires an associated cyclin protein for activity. Various CDK–cyclin complexes regulate different stages of the cell cycle or of the RNA polymerase II transcription cycle.

ORTHOLOGUES

Genes in different species that have arisen directly from a single ancestral gene in the last common ancestor of the species. Orthologous genes often have similar cellular functions.

SYNTHETIC MULTIVULVA (SYNMUV) PHENOTYPE

A mutant phenotype in which hermaphrodites have multiple vulvae that arises from combining class A mutant synMuv alleles with class B mutant synMuv alleles. Mutants of a single class do not have the multivulva phenotype.

SCF UBIQUITIN LIGASE

A multi-subunit ubiquitin ligase (E3) that includes a cullin, CUL1 (for metazoa) or Cdc53 (for budding yeast), which is a scaffold for the complex; a RING-finger protein Rbx1/Roc1/Hrt1, which binds to the ubiquitin-conjugating enzyme (E2); an adaptor protein Skp1; and an F-box protein, which is the substrate-binding component that positions the substrate for ubiquitylation by E2.

CIP/KIP FAMILY

(CDK-inhibitory protein/kinase-inhibitory protein). A family of CDK inhibitors that includes the mammalian p21Cip1, p27Kip1 and p57Kip2, and D. melanogaster Dacapo.

ANAPHASE PROMOTING COMPLEX/CYCLOSOME

(APC/C). A multi-subunit E3 ubiquitin ligase that has an important role in the transition into anaphase, as well as the exit from mitosis and the maintenance of the G1 state.

SEAM CELL

A hypodermal blast cell that produces lateral cuticular ridges (alae) during the L1 larval and adult stages. Seam cells divide during the larval stages to produce more seam cells, hyp7 cells — the main hypodermal (skin) cell for the body — and neurons (in a subset of seam cell lineages).

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Kipreos, E. C. elegans cell cycles: invariance and stem cell divisions. Nat Rev Mol Cell Biol 6, 766–776 (2005). https://doi.org/10.1038/nrm1738

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