Size control: The regulation of cell numbers in animal development

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with fetal spleens, the opposite result is obtained: the total mass of the transplanted spleens attains the mass MRC Laboratory for Molecular Cell Biology and Biology of one normal adult spleen, suggesting that spleen Department growth is mainly controlled by factors outside the spleen University College London (Metcalf, 1964). In neither case are the control mecha-London WC1E 6BT nisms understood. United Kingdom Control of Cell Proliferation Cyclin-dependent protein kinases (Cdks) directly control the eukaryotic cell-division cycle. They are cyclically How is the size of an organism or organ determined? activated to trigger the different phases of the cell cycle Why, for example, are we larger than mice? Although at the right time and in the right sequence. They them-growth can occur by cell enlargement and accumulation selves are controlled by a variety of regulatory proteins: of extracellular matrix, the size of an animal generally cyclins activate them and help direct them to their sub-reflects cell numbers. We are bigger than mice mainly strates; kinases and phosphatases phosphorylate and because we have more cells than a mouse, not because dephosphorylate them, respectively; and Cdk inhibitors our cells are larger. We have more cells because cells block their activity or their assembly with cyclins (Lees, in a developing human divide more times, on average, 1995). than do cells in a developing mouse. What, then, con-Except for the initial cleavages of the zygote and blas-trols how many times a cell divides? The answer is not tomeres, which are apparently cell-autonomous, most known, and, despite its importance, the question has animal cell divisions depend on extracellular growth fac-received little attention. Several recent papers seem tors, which are mainly produced by neighbouring cells. likely to change that. Before considering them, however, The growth factors are required to maintain the cell-I shall briefly review some general aspects of cell number cycle control system: if a cell in culture is deprived of control. such factors, for example, the cell cycle arrests at a Cell number depends on more than just cell prolifera-checkpoint in G1 called the restriction (R) point, and the tion. It also depends on cell death and, in some organs, cell enters a modified G1 state (G0), in which some of on cell immigration, emigration, or both. Division, death, the Cdks and cyclins disappear. and migration all depend on intracellular mechanisms The dependence of animal cell division on signals that are regulated by extracellular signaling molecules from other cells helps to ensure that a cell divides only produced by other cells. The signaling molecules can when another cell is needed. When part of the adult liver either activate or inhibit the intracellular mechanisms; is removed, for example, cell proliferation returns the they can operate locally or systemically and can be liver to normal size. In regenerating limbs, and probably soluble, bound to cell surfaces, or associated with the in other regenerating and developing tissues also, if a extracellular matrix. The challenge is to understand how disparity occurs in the positional values of neighbouring the extracellular signals and intracellular mechanisms cells, proliferation produces cells with intermediate po-interact to ensure that each organ contains the right sitional values, thereby creating a continuous and ap-numbers of each cell type. proriate cell pattern. It remains a mystery how such The right number of cells depends on cell size, which disparities are detected by cells and how they stimulate in turn depends on the amount of DNA in the nucleus. cell proliferation. The cells in a tetraploid salamander, for example, are A large effort has been devoted to identifying both four times the volume of those in a haploid salamander, the extracellular signaling molecules that stimulate cell yet the corresponding organs in the two animals are proliferation and the intracellular signaling pathways the same size because the tetraploid organs contain a that they activate. By contrast, there has been relatively quarter as many cells as the haploid (Frankhauser, 1952). little exploration of the mechanisms responsible for Clearly, cell number control is not merely a matter of stopping cell proliferation at the appropriate point during counting cells or cell divisions. regeneration or development. The stopping mecha-Systemic versus Local Control nisms are important, as they can influence both cell Systemic controls help coordinate the growth of differ-numbers and the timing of differentiation. ent organs during development. In vertebrates, for ex-In part at least, the stopping mechanisms are cell-ample, the anterior pituitary gland seceretes growth hor-intrinsic and depend on the cell's history. In principle, mone, which stimulates growth principally by inducing such an intrinsic mechanism could depend on a de-the production of insulin-like growth factor 1 (IGF-1) by crease in a positive intracellular regulator that is required the liver and other organs. IGF-1 in turn promotes cell to keep the cell dividing, an increase in a negative intra-survival in many tissues and cell proliferation in some. cellular regulator that inhibits cell-cycle progression, or The importance of systemic controls on growth can both. An example of the first mechanism is seen in the vary greatly between organs. If one transplants multiple first cells that stop dividing at the cellular blastoderm fetal thymus glands into a developing mouse, each stage of Drosophila development: these cells arrest in grows to its normal adult size, suggesting that their the G2 phase of the cell cycle because the supply of growth is mainly controlled locally within the thymus maternal String protein—the phosphatase required to activate the mitotic Cdk (Cdc-2)—runs out, so that the (Metcalf, 1963). If one performs the same experiment Cell 174 cells cannot progress into M phase (Edgar and O'Farrell, 1990). A possible example of the second mechanism is seen in fibroblast senescence, where accumulation of the Cdk inhibitor p16 Ink4 (p16) may be in part responsible for limiting the number of times normal fibroblasts divide in culture when stimulated by serum: early-passage hu-man fibroblasts express low levels of p16, while late-passage, senescent ones express high levels (Hara et al., 1996), and embryo fibroblasts from p16 Ϫ/Ϫ mice readily escape such senescence (Serrano et al., 1996). Control of Cell Survival and Cell Death Just as animal cells need signals from other cells to divide, so most seem to need signals from other cells to survive. If deprived of such signals, the cells activate an intrinsic death program and kill themselves—a pro-cess called programmed cell death (PCD). Dependence on survival signals may help ensure that a cell survives only where and when it is needed. PCD is mediated by a proteolytic cascade, involving a family of cysteine Figure 1. Some Components of the Cell-Cycle Control System That




Raff, M. C. (1996, July 26). Size control: The regulation of cell numbers in animal development. Cell. Cell Press.

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