Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells

Intestinal stem cells (ISCs) in the adult Drosophila melanogaster midgut can respond to damage and support repair. We demonstrate in this paper that the tuberous sclerosis complex (TSC) plays a critical role in balancing ISC growth and division. Previous studies have shown that imaginal disc cells that are mutant for TSC have increased rates of growth and division. However, we report in this paper that loss of TSC in the adult Drosophila midgut results in the formation of much larger ISCs that have halted cell division. These mutant ISCs expressed proper stem cell markers, did not differentiate, and had defects in multiple steps of the cell cycle. Slowing the growth by feeding rapamycin or reducing Myc was sufficient to rescue the division defect. The TSC mutant guts had a thinner epithelial structure than wild-type tissues, and the mutant flies were more susceptible to tissue damage. Therefore, we have uncovered a context-dependent phenotype of TSC mutants in adult ISCs, such that the excessive growth leads to inhibition of division.     

Design principles of tissue organisation: How single cells coordinate across scales

Cells act as building blocks of multicellular organisms, forming higher-order structures at different biological scales. Niches, tissues and, ultimately, entire organisms consist of single cells that remain in constant communication. Emergence of developmental patterns and tissue architecture thus relies on single cells acting as a collective, coordinating growth, migration, cell fate transitions and cell type sorting. For this, information has to be transmitted forward from cells to tissues and fed back to the individual cell to allow dynamic and robust coordination. Here, we define the design principles of tissue organisation integrating chemical, genetic and mechanical cues. We also review the state-of-the-art technologies used for dissecting collective cellular behaviours at single cell– and tissue-level resolution. We finally outline future challenges that lie in a comprehensive understanding of how single cells coordinate across biological scales to insure robust development, homoeostasis and regeneration of tissues.     

Mitochondrial growth and division during the cell cycle in HeLa cells

The growth and division of mitochondria during the cell cycle was investigated by a morphometric analysis of electron micrographs of synchronized HeLa cells. The ratio of total outer membrane contour length to cytoplasmic area did not vary significantly during the cell cycle, implying a continuous growth of the mitochondrial outer membrane. The mean fraction of cytoplasmic area occupied by mitochondrial profiles was likewise found to remain constant, indicating that the increase in total mitochondrial volume per cell occurs continuously during interphase, in such a way that the mitochondrial complement occupies a constant fraction( approximately 10-11(percent)) of the volume of the cytoplasm. The mean area, outer membrane contour length, and axis ratio of the mitochondrial profiles also did not vary appreciably during the cell cycle; furthermore, the close similarity of the frequency distributions of these parameters for the six experimental time-points suggested a stable mitochondrial shape distribution. The constancy of both the mean mitochondrial profile area and the number of mitochondrial profiles per unit of cytoplasmic area was interpreted to indicate the continuous division of mitochondria at the level of the cell population. Furthermore, no evidence was found for the occurrence of synchronous mitochondrial growth and division within individual cells. Thus, it appears that, in HeLa cells, there is no fixed temporal relationship between the growth and division of mitochondria and the events of the cell cycle. A number of statistical methods were developed for the purpose of making numerical estimates of certain three-dimensional cellular and mitochondrial parameters. Mean cellular and cytoplasmic volumes were calculated for the six time-points; both exhibited a nonlinear, approx. twofold increase. A comparison of the axis ratio distributions of the mitochondrial profiles with theoretical distributions expected from random sectioning of bodies of various three-dimensional shapes allowed the derivation of an "average" mitochondrial shape. This, in turn, permitted calculations to be made which expressed the two-dimensional results in three-dimensional terms. Thus, the estimated values for the number of mitochondria per unit of cytoplasmic volume and for the mean mitochondrial volume were found to remain constant during the cell cycle, while the estimated number of mitochondria per cell increase approx. twofold in an essentially continuous manner.     

A general framework for modeling growth and division of mammalian cells

Background  

Modeling the cell-division cycle has been practiced for many years. As time has progressed, this work has gone from understanding the basic principles to addressing distinct biological problems, e.g., the nature of the restriction point, how checkpoints operate, the nonlinear dynamics of the cell cycle, the effect of localization, etc. Most models consist of coupled ordinary differential equations developed by the researchers, restricted to deal with the interactions of a limited number of molecules. In the future, cell-cycle modeling--and indeed all modeling of complex biologic processes--will increase in scope and detail.     

Cell growth and division in relation to differentiation of mouse erythroleukemia cells

Addition of certain inhibitors of RNA or protein synthesis to cells cultured in 20% serum, but not 5% serum, induces the differentiation of mouse erythroleukemia cells. Differentiation also was induced by culture at a low serum concentration (0.1%) to starve cells to quiescence, then inducing division by exposing cells to either of two high-pH regimes.     

Coupled oscillators coordinate collective germline growth

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Asymmetric cell division and neoplastic growth

Asymmetric division was formed as an evolutionary conserved mechanism of self-maintenance of cellular populations and creation of a variety of cell types during ontogenesis. Asymmetric division enables a special mechanism of determinant segregation, which further defines development of daughter cells. As a result two unequal cells are developed. Recent research demonstrates the interplay of disturbed asymmetric division of stem cells and tumorigenesis. Genes implicated in cell’s polarization and normal progression of asymmetric mitosis were identified in Drosophila. Other genes regulating asymmetric mitosis were described as tumor suppressors, and their mutations were shown to initiate neoplastic growth. Comparative study of gene expression suggests that the disturbance of asymmetric division might be one of the reasons for neoplasm progression in vertebrates.     

PAR-4 and anillin regulate myosin to coordinate spindle and furrow position during asymmetric division

During asymmetric cell division, the mitotic spindle and polarized myosin can both determine the position of the cytokinetic furrow. However, how cells coordinate signals from the spindle and myosin to ensure that cleavage occurs through the spindle midzone is unknown. Here, we identify a novel pathway that is essential to inhibit myosin and coordinate furrow and spindle positions during asymmetric division. In Caenorhabditis elegans one-cell embryos, myosin localizes at the anterior cortex whereas the mitotic spindle localizes toward the posterior. We find that PAR-4/LKB1 impinges on myosin via two pathways, an anillin-dependent pathway that also responds to the cullin CUL-5 and an anillin-independent pathway involving the kinase PIG-1/MELK. In the absence of both PIG-1/MELK and the anillin ANI-1, myosin accumulates at the anterior cortex and induces a strong displacement of the furrow toward the anterior, which can lead to DNA segregation defects. Regulation of asymmetrically localized myosin is thus critical to ensure that furrow and spindle midzone positions coincide throughout cytokinesis.     

Cell division and cell growth in size

Summary and conclusion The coefficient of correlation between cell length and percentage mitosis in root-tips ofZea mays was found to be high and negative: r=–0·577±0·075. This value taken together with correlated data justifies the generality that cell division and cell size are inversely related. An analysis of the bases of the relation brings the conclusion that in an increasing cell population where growth in cell number and growth in cell size are taking place simultaneously, cell division is the independent and cell size the dependent variable. That is to say, other things being equal, the size of the cells is a result of the rate of cell multiplication. The explanation of this is given in the text.     

A growth and division model for retinoblastoma

A stochastic growth and division model for studying a two hit cancer is developed and applied to retinoblastoma. Retinoblastoma occurs if both genes coding for a tumor suppressor protein on homologous chromosomes become defective. Germinal cases occur when a patient or carrier, born with one defective gene, suffers a second insult to any progeny retinal cell. Somatic cases are far less likely as two hits to the same cell during development are required. Details of the disease, germinal or somatic, unilateral or bilateral, in combination with case data allow for the estimation of the two parameters of the model: mutation rate, estimated at p=7x10(-7) per chromosome per cell division, and carrier frequency, estimated at f=40 per million. The model indicates that carriers of the disease arise from similar mutations to germ cells; in particular, heridary transmission can occur for only a generation or two before dying out. The results show that a stochastic simulation of a multi-hit cancer is feasible and may predict tumor growth dynamics. A simulation run will have to consist of a few million cells in order to observe even a small number of mutations. And several dozens such runs will have to be simulated.