Characterization of the unusually rapid cell cycles during rat gastrulation.

The onset of gastrulation in rodents is associated with the start of differentiation within the embryo proper and a dramatic increase in the rate of growth and proliferation. We have determined the duration of the cell cycle for mesodermal and ectodermal cells of rat embryos during gastrulation (days 8.5 to 9.5 of gestation) using a stathmokinetic analysis. These embryonic cells are the most rapidly dividing mammalian cells yet described. Most cells of the ectoderm and mesoderm had a cell cycle time of 7 to 7.5 hours, but the cells of the primitive streak divided every 3 to 3.5 hours. Total cell cycle time was reduced by shortening S and G2, as well as G1, in contrast to cells later in development, when cell cycle duration is modulated largely by varying the length of G1. In the ectoderm and mesoderm, G1 was 1.5 to 2 hours, S was 3.5 to 4 hours, and G2 was 30 to 40 minutes. G1, S and G2 were shortened even further in the cells of the primitive streak: G1 was less than 30 minutes, S was 2 to 2.75 hours, and G2 was less than 20 minutes. Thus, progress of cells through all phases of the cell cycle is extensively modified during rodent embryogenesis. Specifically, the increased growth rate during gastrulation is associated with radical changes in cell cycle structure and duration. Further, the commitment of cells to become mesoderm and endoderm by entering the primitive streak is associated with expression of a very short cell cycle during transit of the primitive streak, such that developmental decisions determining germ layer fate are reflected in differences in cell cycle regulation.

[1]  M. Cikes Relationship between growth rate, cell volume, cell cycle kinetics, and antigenic properties of cultured murine lymphoma cells. , 1970, Journal of the National Cancer Institute.

[2]  P. Mirkes,et al.  Cell cycle analysis in the cardiac and neuroepithelial tissues of day 10 rat embryos and the effects of phosphoramide mustard, the major teratogenic metabolite of cyclophosphamide. , 1989, Teratology.

[3]  M. Loeffler,et al.  Intestinal Cell Proliferation. I. A Comprehensive Model of Steady‐State Proliferation In the Crypt , 1986, Cell and tissue kinetics.

[4]  R. W. Morgan,et al.  Changes in the cell cycle during early amphibian development , 1966 .

[5]  C. Downes,et al.  Caffeine overcomes a restriction point associated with DNA replication, but does not accelerate mitosis , 1990, The Journal of cell biology.

[6]  J. Abramczuk,et al.  DNA synthesis in the second and third cell cycles of mouse preimplantation development. A cytophotometric study. , 1978, Experimental cell research.

[7]  V. Foe,et al.  Mitotic domains reveal early commitment of cells in Drosophila embryos. , 1989, Development.

[8]  B. Alberts,et al.  daughterless-abo-like, a Drosophila maternal-effect mutation that exhibits abnormal centrosome separation during the late blastoderm divisions. , 1990, Development.

[9]  M. Johnson,et al.  The relationship between cleavage, DNA replication, and gene expression in the mouse 2-cell embryo. , 1984, Journal of embryology and experimental morphology.

[10]  W. Hittelman,et al.  Bleomycin-induced damage in prematurely condensed chromosomes and its relationship to cell cycle progression in CHO cells. , 1974, Cancer research.

[11]  M. Kirschner,et al.  The events of the midblastula transition in Xenopus are regulated by changes in the cell cycle , 1987, Cell.

[12]  P. O’Farrell,et al.  The three postblastoderm cell cycles of Drosophila embryogenesis are regulated in G2 by string , 1990, Cell.

[13]  M. Kirschner,et al.  A major developmental transition in early xenopus embryos: II. control of the onset of transcription , 1982, Cell.

[14]  D. Rappolee,et al.  Insulin-like growth factor II acts through an endogenous growth pathway regulated by imprinting in early mouse embryos. , 1992, Genes & development.

[15]  R. Tobey Different drugs arrest cells at a number of distinct stages in G2 , 1975, Nature.

[16]  W. Hittelman,et al.  Premature chromosome condensation. I. Visualization of x-ray-induced chromosome damage in interphase cells. , 1974, Mutation research.

[17]  S. Kauffman Lengthening of the generation cycle during embryonic differentiation of the mouse neural tube. , 1968, Experimental cell research.

[18]  R. Pedersen,et al.  Cell fate, morphogenetic movement and population kinetics of embryonic endoderm at the time of germ layer formation in the mouse. , 1987, Development.

[19]  L. Hartwell,et al.  The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. , 1988, Science.

[20]  R. Tobey,et al.  THE EFFECT OF THYMIDINE ON THE DURATION OF G1 IN CHINESE HAMSTER CELLS , 1967, The Journal of cell biology.

[21]  S. Howlett,et al.  Sequence and regulation of morphological and molecular events during the first cell cycle of mouse embryogenesis. , 1985, Journal of embryology and experimental morphology.

[22]  D. Glover Mitosis in the Drosophila embryo--in and out of control. , 1991, Trends in genetics : TIG.

[23]  Paul Russell,et al.  cdc25 + functions as an inducer in the mitotic control of fission yeast , 1986, Cell.

[24]  D. Hogness,et al.  The units of DNA replication in Drosophila melanogaster chromosomes. , 1974, Cold Spring Harbor symposia on quantitative biology.

[25]  M. Kirschner,et al.  A major developmental transition in early xenopus embryos: I. characterization and timing of cellular changes at the midblastula stage , 1982, Cell.

[26]  P. O’Farrell,et al.  Genetic control of cell division patterns in the Drosophila embryo , 1989, Cell.

[27]  A. Pardee G1 events and regulation of cell proliferation. , 1989, Science.

[28]  J. Raff,et al.  Nuclear and cytoplasmic mitotic cycles continue in Drosophila embryos in which DNA synthesis is inhibited with aphidicolin , 1988, The Journal of cell biology.

[29]  P. O’Farrell,et al.  Directing cell division during development. , 1989, Science.

[30]  M. Dasso,et al.  Completion of DNA replication is monitored by a feedback system that controls the initiation of mitosis in vitro: Studies in Xenopus , 1990, Cell.

[31]  D. Solter,et al.  Cell cycle analysis in the mouse EGG-cylinder. , 1971, Experimental cell research.

[32]  J. Rossant,et al.  Mechanism of size regulation in mouse embryo aggregates. , 1982, Journal of embryology and experimental morphology.

[33]  F. Cross,et al.  Simple and complex cell cycles. , 1989, Annual review of cell biology.

[34]  C. Nüsslein-Volhard,et al.  Altered mitotic domains reveal fate map changes in Drosophila embryos mutant for zygotic dorsoventral patterning genes. , 1992, Development.

[35]  A. Pardee,et al.  Mechanism by which caffeine potentiates lethality of nitrogen mustard. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Poelmann Differential mitosis and degeneration patterns in relation to the alterations in the shape of the embryonic ectoderm of early post-implantation mouse embryos. , 1980, Journal of embryology and experimental morphology.

[37]  S. McKnight,et al.  Electron microscopic analysis of chromatin replication in the cellular blastoderm drosophila melanogaster embryo , 1977, Cell.

[38]  F. Luthardt,et al.  DNA synthesis in developing two-cell mouse embryos. , 1975, Developmental biology.

[39]  M. Snow Gastrulation in the mouse: Growth and regionalization of the epiblast , 1977 .

[40]  M. Loeffler,et al.  Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. , 1990, Development.

[41]  L. Hartwell,et al.  Checkpoints: controls that ensure the order of cell cycle events. , 1989, Science.

[42]  D A Agard,et al.  Direct cell lineage analysis in Drosophila melanogaster by time-lapse, three-dimensional optical microscopy of living embryos , 1989, The Journal of cell biology.

[43]  M. Rabinowitz Studies on the cytology and early embryology of the egg of Drosophila melanogaster , 1941 .

[44]  J. M. Baden,et al.  A new method for explanting early postimplantation rat embryos for culture. , 1991, Teratology.

[45]  G. Martin,et al.  Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. , 1992, Development.

[46]  L. Hartwell,et al.  Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae. , 1985, Genetics.

[47]  S. Howlett A set of proteins showing cell cycle dependent modification in the early mouse embryo , 1986, Cell.

[48]  A. Zetterberg,et al.  Cytotoxic effects of cell cycle phase specific agents: result of cell cycle perturbation. , 1990, Cancer research.

[49]  R. Pedersen,et al.  Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. , 1991, Development.