Key Points
-
The size of an organism is controlled by regulating the growth, division and death rates of cells. Whereas we know much about the mechanisms within a cell that control these parameters, how these pathways are then used to control cell number and size has remained more elusive.
-
Cell growth and division are often tightly coupled. For example, cyclin D mutations are implicated in size regulation in flies, mammals and plants.
-
When cell size is constant, initial tissue size can be controlled by regulating cell number by allowing cells to divide a certain number of times or for a specified amount of time. A counting mechanism in Xenopus laevis uses a fixed amount of a titratable factor within the egg to regulate the number of divisions. Oligodendrocytes use an intrinsic timer to stop division after a fixed time interval.
-
Cell number can be sensed by having cells secrete a factor that they simultaneously sense. Examples of this are found in bacteria, social amoebae and mammals. Both muscle and thyroid tissues, for example, use secreted factors as part of a negative-feedback loop to control growth.
-
Other secreted factors and signal-transduction pathways also regulate growth and cell division. For example, children who lack growth hormone have growth defects, which can be corrected with growth hormone treatments. Studies in mammals, flies and worms suggest a conserved role for the insulin pathway in regulating growth.
-
There are mechanisms that then mediate the breakup of a tissue into subgroups of defined size. For example, in Drosophila, gradients of morphogens specify subregions of the egg. In Dictyostelium, a secreted signal regulating cell–cell adhesion regulates the breakup of a tissue into subgroups.
Abstract
Size regulation is a never-ending problem. Many of us worry that parts of ourselves are too big whereas other parts are too small. How organisms — and their tissues — are programmed to be a specific size, how this size is maintained, and what might cause something to become the wrong size, are key problems in developmental biology. But what are the mechanisms that regulate the size of multicellular structures?
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Haldane, J. B. S. in Possible Worlds and Other Papers 20–28 (Harper & Brothers, New York, 1928).
Colinvaux, P. Why Big Fierce Animals Are Rare. An Ecologist's Perspective (Princeton University Press, Princeton, New Jersey, 1978).
Su, T. T. The regulation of cell growth and proliferation during organogenesis. In Vivo 14, 141–148 ( 2000).
Conlon, I. & Raff, M. Size control in animal development . Cell 96, 235–244 (1999).
Galitski, T., Saldanha, A., Styles, C., Lander, E. & Fink, G. Ploidy regulation of gene expression. Science 285, 251–254 ( 1999).
Fankhauser, G. The effects of changes in chromosome number on amphibian development. Quart. Rev. Biol. 20, 20–78 (1945).
Weigmann, K., Cohen, S. M. & Lehner, C. F. Cell cycle progression, growth, and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase. Development 124, 3555–3563 (1997).
Neufeld, T. P., de la Cruz, A. F., Johnston, L. A. & Edgar, B. A. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183–1193 ( 1998).
Sulston, J., Schierenberg, E., White, J. & Thomson, J. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64–119 ( 1983).
Newport, J. & Kirschner, M. A major developmental transition in early Xenopus embryos: I. Characterization and timing of cellular changes at the midblastula stage. Cell 30, 675–686 (1982).
Newport, J. & Kirschner, M. A major developmental transition in early Xenopus embryos: II. Control of the onset of transcription . Cell 30, 687–696 (1982).References 10 and 11 show that a cell division counter can function by titrating a fixed amount of a compound with DNA for the dividing cells.
Kim, S. K. & Kaiser, D. Cell motility is required for the transmission of C-factor, an intercellular signal that coordinates fruiting body morphogenesis of Myxococcus xanthus. Genes Dev. 4, 896–905 (1990).
Kim, S. K. & Kaiser, D. C-factor: Cell–cell signaling protein required for fruiting body morphogenesis of M. xanthus. Cell 61, 19–26 ( 1990).
Kaplan, H. B. & Plamann, L. A Myxococcus xanthus cell density-sensing system required for multicellular development. FEMS Microbiol. Lett. 139, 89–95 (1996).
Eberhard, A. et al. Structural identification of autoinducer of Photobacterium fischeri luciferase. Biochemistry 20, 2444–2449 (1981).
Grossman, A. D. & Losick, R. Extracellular control of spore formation in Bacillus subtilis. Proc. Natl Acad. Sci. USA 85, 4369–4373 ( 1988).
Kaplan, H. B. Cell–cell interactions that direct fruiting body development in Myxococcus xanthus. Curr. Opin. Genet. Dev. 1, 363–369 (1991).
Mehdy, M. C. & Firtel, R. A. A secreted factor and cyclic AMP jointly regulate cell-type–specific gene expression in Dictyostelium discoideum. Mol. Cell. Biol. 5, 705– 713 (1985).
Yuen, I. S. & Gomer, R. H. Cell density-sensing in Dictyostelium by means of the accumulation rate, diffusion coefficient and activity threshold of a protein secreted by starved cells. J. Theor. Biol. 167, 273–282 ( 1994).
Clarke, M. & Gomer, R. H. PSF and CMF, autocrine factors that regulate gene expression during growth and early development of Dictyostelium . Experientia 51, 1124– 1134 (1995).
Palmiter, R. D., Norstedt, G., Gelinas, R. E., Hammer, R. E. & Brinster, R. L. Metallothionein-human GH fusion genes stimulate growth of mice. Science 222, 809–814 (1983).A major advance in regulating the size of an animal.
Voss, L. D. Growth hormone therapy for the short normal child: who needs it and who wants it? The case against growth hormone therapy. J. Pediatr. 136, 103–106 (2000).
Sandberg, D. E. Should short children who are not deficient in growth hormone be treated? West. J. Med. 172, 186– 189 (2000).
Weinkove, D. & Leevers, S. J. The genetic control of organ growth: insights from Drosophila. Curr. Opin. Genet. Dev. 10, 75–80 ( 2000).
Coelho, C. M. & Leevers, S. J. Do growth and cell division rates determine cell size in multicellular organisms? J. Cell Sci. 113, 2927–2934 (2000).
Chen, C., Jack, J. & Garofalo, R. S. The Drosophila insulin receptor is required for normal growth. Endocrinology 137, 846 –856 (1996).
Bohni, R. et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97, 865–875 (1999).
Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E. & Waterfield, M. D. The Drosophila phosphoinositide 3-kinase DP110 promotes cell growth. EMBO J. 15, 6584–6594 (1996).
Montagne, J. et al. Drosophila S6 kinase; a regulator of cell size. Science 285, 2126–2129 ( 1999).
Weinkove, D., Neufeld, T., Twardzik, T., Waterfield, M. & Leevers, S. Regulation of imaginal disc cell size, cell number and organ size by Drosophila class I(A) phosphoinositide 3-kinase and its adapter. Curr. Biol. 9, 1019–1029 (1999).
Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319–1322 (1997).
Wolkow, C., Kimura, K., Lee, M. & Ruvkun, G. Regulation of C. elegans life-span by insulin-like signaling in the nervous system. Science 290, 147–150 ( 2000).
Nakayama, K. et al. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors . Cell 85, 707–720 (1996).
Franklin, D. et al. CDK inhibitors p18INK4c and p27Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev. 12, 2899– 2911 (1998).
Kiyokawa, H. et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27kip1. Cell 85, 721–732 (1996).
Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice . Cell 85, 733–744 (1996).
Meyer, C. et al. Drosophila cdk4 is required for normal growth and is dispensable for cell cycle progression. EMBO J. 19, 4533–4542 (2000).
Datar, S., Jacobs, H., de La Cruz, A., Lehner, C. & Edgar, B. The Drosophila cyclin D–cdk4 complex promotes cellular growth. EMBO J. 19, 4543–4554 (2000).
Preisig, P. A cell cycle-dependent mechanism of renal tubule epithelial cell hypertrophy . Kidney Int. 56, 1193– 1198 (1999).
Braam, J. & Davis, R. W. Rain-, wind-, and touch-induced expression of calmodulin and calmodulin-related genes in Arabidopsis. Cell 60, 357–364 ( 1990).
Cockcroft, C. E., den Boer, B. G., Healy, J. M. & Murray, J. A. Cyclin D control of growth rate in plants. Nature 405 , 575–579 (2000).
Micalopoulos, G. K. & DeFrances, M. C. Liver regeneration . Science 276, 60–66 (1997).
Meir, S. Development of the chick embryo mesoblast. Dev. Biol. 73, 25–45 (1979).
Jaing, T.-X., Jung, H.-S., Widelitz, R. B. & Chuong, C.-M. Self-organization of periodic patterns by dissociated feather mesenchymal cells and the regulation of size, number and spacing of primordia. Development 126, 4997–5009 (1999).
Rawls, A., Wilson–Rawls, J. & Olson, E. N. Genetic regulation of somite formation. Curr. Top. Dev. Biol. 47, 131–154 (2000).
Metcalf, D. Restricted growth capacity of multiple spleen grafts. Transplantation 2, 387–392 ( 1964).
Lee, S. & McPherron, A. Myostatin and the control of skeletal muscle mass. Curr. Opin. Genet. Dev. 9, 604–607 (1999).
Thomas, M. et al. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J. Biol. Chem. 275, 40235–40243 (2000).
McPherron, A. & Lee, S. Double muscling in cattle due to mutations in the myostatin gene. Proc. Natl Acad. Sci. USA 94 , 12457–12461 (1997).
McPherron, A. C., Lawler, A. M. & Lee, S. -J. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387, 83–90 (1997).An excellent example of a secreted-factor directly inhibiting the growth of the secreted cells.
De Groot, L. J. in Control of the Thyroid Gland (eds Ekholm, R., Kohn, L. D. & Wollman, S. H.) 5–10 (Plenum, New York, 1989).
Larsen, P. R. in Control of the Thyroid Gland (eds Ekholm, R., Kohn, L. D. & Wollman, S. H.) 11–26 (Plenum, New York, 1989).
Eggo, M. & Burrow, G. N. in Control of the Thyroid Gland (eds Ekholm, R., Kohn, L. D. & Wollman, S. H.) 327– 339 (Plenum, New York, 1989).
Dumont, J. E. et al. in Control of the Thyroid Gland (eds Ekholm, R., Kohn, L. D. & Wollman, S. H.) 357–372 (Plenum, New York, 1989).
Schwartz, M., Woods, S., Porte, D. J., Seeley, R. & Baskin, D. Central nervous system control of food intake. Nature 404, 661–671 ( 2000).
Ahima, R. S. Leptin and the neuroendocrinology of fasting. Front. Horm. Res. 26, 42–56 ( 2000).
St. Johnston, D. & Nusslein-Volhard, C. The origin of pattern and polarity in the Drosophila embryo. Cell 68, 201–219 ( 1992).Lucid description of the Drosophila patterning mechanism.
Loomis, W. F. Dictyostelium discoideum: A Developmental System (Academic, New York, 1975).
Loomis, W. F. Development of Dictyostelium discoideum. (Academic, New York, 1982).
Bonner, J. T. & Hoffman, M. E. Evidence for a substance responsible for spacing pattern of aggregation and fruiting bodies in the cellular slime mold. J. Embryol. Exp. Morphol. 11, 571– 589 (1963).
Kopachik, W. J. Size regulation in Dictyostelium. J. Embryol. Exp. Morphol. 68, 23–35 ( 1982).
Brock, D. A. & Gomer, R. H. A cell-counting factor regulating structure size in Dictyostelium. Genes Dev. 13, 1960–1969 (1999).
Brown, J. M. & Firtel, R. A. Just the right size: Cell counting in Dictyostelium. Trends Genet. 16, 191–193 (2000).
Spann, T. P., Brock, D. A., Lindsey, D. F., Wood, S. A. & Gomer, R. H. Mutagenesis and gene identification in Dictyostelium by shotgun antisense. Proc. Natl Acad. Sci. USA 93, 5003–5007 ( 1996).
Brock, D. A. et al. A Dictyostelium mutant with defective aggregate size determination. Development 122, 2569– 2578 (1996).
Goodman, C. The likeness of being: phylogenetically conserved molecular mechanisms of growth cone guidance. Cell 78, 353– 356 (1994).
Radice, G. et al. Developmental defects in mouse embryos lacking N-cadherin . Dev. Biol. 181, 64–78 (1997).
Myat, M. & Andrew, D. Organ shape in the Drosophila salivary gland is controlled by regulated, sequential internalization of the primordia. Development 127, 679– 691 (2000).
Garcia-Castro, M. I., Vielmetter, E. & Bronner-Fraser, M. N-cadherin, a cell adhesion molecule involved in establishment of embryonic left–right asymmetry. Science 288 , 1047–1051 (2000).
Kamboj, R. K., Lam, T. Y. & Siu, C. H. Regulation of slug size by the cell adhesion molecule gp80 in Dictyostelium discoideum. Cell Reg. 1, 715–729 (1990).
Siu, C. H. & Kamboj, R. K. Cell–cell adhesion and morphogenesis in Dictyostelium discoideum. Dev. Genet. 11, 377–387 (1990).
Roisin-Bouffay, C., Jang, W. & Gomer, R. H. A precise group size in Dictyostelium is generated by a cell-counting factor modulating cell–cell adhesion. Mol. Cell 6, 953–959 ( 2000).
Gao, F., Apperly, J. & Raff, M. Cell-intrinsic timers and thyroid hormone regulate the probability of cell-cycle withdrawal and differentiation of oligodendrocyte precursor cells. Dev. Biol. 197, 54– 66 (1998).
Kondo, T. & Raff, M. Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development 127, 2989–2998 (2000).
Durand, B. & Raff, M. A cell-intrinsic timer that operates during oligodendrocyte development. BioEssays 22, 64–71 (2000).Elegant description of a timer mechanism regulating how long a group of cells can continue dividing.
Durand, B., Fero, N. L., Roberts, J. M. & Raff, M. C. p27Kip1 alters the response of cells to nitrogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation . Curr. Biol. 8, 431–440 (1998).
Raff, M., Lillien, L., Richardson, W., Burnem, J. & Noble, M. Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture . Nature 333, 562–565 (1988).
Barres, B., Lazar, M. & Raff, M. A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120, 1097–1108 (1994).
Burton, P. B. J., Raff, M. C., Kerr, P., Yacoub, M. H. & Barton, P. J. R. An intrinsic timer that controls cell-cycle withdrawal in cultured cardiac myocytes. Dev. Biol. 216, 659–670 (1999).
Calver, A. et al. Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 20, 869– 882 1998).
Burne, J. F., Staple, J. K. & Raff, M. C. Glial cells are increased proportionally in transgenic optic nerves with increased numbers of axons. J. Neurosci. 16, 2064–2073 (1996).
Barres, B. A. & Raff, M. C. Axonal control of oligodendrocyte development. J. Cell Biol. 147, 1123– 1128 (1999).
Bullough, W. S. & Laurence, E. B. Mitotic control by internal secretion: The role of the chalone–adrenalin complex. Exp. Cell Res. 33, 176–194 (1964).
Bullough, W. S. Mitotic and function homeostasis: a speculative review. Cancer Res. 25, 1683–1727 ( 1965).
Boldingh, W. & Laurence, E. Extraction, purification and preliminary characterization of the epidermal chalone: A tissue specific mitotic inhibitor obtained from vertebrate skin. Eur. J. Biochem. 5, 191–198 (1968).
Sassier, P. & Bergeron, M. Specific inhibition of cell proliferation in the mouse intestine by an aqueous extract of rabbit small intestine. Cell Tissue Kinet. 10, 223–231 (1977).
Barfod, N. M. Isolation and partial identification of eight endogenous G1 inhibitors of JB–1 ascites tumor cell proliferation. Cancer Res. 42, 2420–2425 (1982).
Saetren, H. A principle of autoregulation of growth. Production of organ specific mitose-inhibitors in kidney and liver. Exp. Cell Res. 11, 229–232 (1956).
Bullough, W. S., Hewett, C. L. & Laurence, E. B. The epidermal chalone: A preliminary attempt at isolation . Exp. Cell Res. 36, 192– 200 (1964).
Richter, K. et al. Epidermal G1-chalone and transforming growth factor-β are two different endogenous inhibitors of epidermal cell proliferation. J. Cell Physiol. 142, 496–504 (1990).
Hodges, A. Alan Turing: The Enigma (Simon & Schuster, New York, 1983).
Turing, A. M. The chemical basis of morphogenesis. Phil. Trans. R. Soc. (Lond.) 237, 37–72 ( 1952).A tour de force of theoretical biology. Turing's genius, ability to explain things simply, and kind personality are evident in this paper.
Meinhardt, H. Models of Biological Pattern Formation (Academic, London, 1982).
McNally, J. G. & Cox, E. C. Geometry and spatial patterns in Polysphondylium pallidum. Dev. Genet. 9, 663–672 (1988).
Sawai, S., Maeda, Y. & Swada, Y. Spontaneous symmetry breaking Turing-type pattern formation in a confined Dictyostelium cell mass. Phys. Rev. Lett. 85, 2212–2215 ( 2000).
Smith, K. M., Gee, L. & Bode, H. R. HyAlx, an aristaless-related gene, is involved in tentacle formation in hydra. Development 127, 4743–4752 (2000).
Gueron, S., Levin, S. A. & Rubenstein, D. I. The dynamics of herds: From individuals to aggregations . J. Theor. Biol. 182, 85– 98 (1996).
Okubo, A. in Advances in Biophysics (eds Kotani, M. & Noda, H.) 1– 87 (Japan Sci. Soc., Tokyo, 1986).
Flierl, G., Grunbaum, D., Levins, S. & Olson, D. From individuals to aggregations: the interplay between behavior and physics. J. Theor. Biol. 196, 397–454 (1999).
Bonabeau, E., Dagorn, L. & Freon, P. Scaling in animal group-size distributions. Proc. Natl Acad. Sci. USA 96, 4472– 4477 (1999).
Fuqua, W. C., Winans, S. C. & Greenberg, E. P. Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators. J. Bacteriol. 176, 269–275 ( 1994).
Piper, K. R., von Bodiman, S. B. & Farrand, S. K. Conjugation factor of Agrobacterium tumefaciens regulated Ti plasmid transfer by autoinduction. Nature 362, 448–450 (1993).
Kuspa, A., Plamann, L. & Kaiser, D. Identification of heat-stable A-factor from Myxococcus xanthus. J. Bacteriol. 174, 3319– 3326 (1992).
Magnuson, T., Solomon, J. & Grossman, A. D. Biochemical and genetic characterization of a competence pheromone from B. subtilis. Cell 77, 207–216 (1994).
Jain, R., Yuen, I. S., Taphouse, C. R. & Gomer, R. H. A density-sensing factor controls development in Dictyostelium. Genes Dev. 6, 390–400 ( 1992).
Jain, R. & Gomer, R. H. A developmentally regulated cell surface receptor for a density-sensing factor in Dictyostelium. J. Biol. Chem. 269, 9128–9136 (1994).
Van Haastert, P. J. M., Bishop, J. D. & Gomer, R. H. The cell density factor CMF regulates the chemoattractant receptor cAR1 in Dictyostelium. J. Cell Biol. 134, 1543–1549 (1996).
Brazill, D. T., Lindsey, D. F., Bishop, J. D. & Gomer, R. H. Cell density sensing mediated by a G protein-coupled receptor activating phospholipase C. J. Biol. Chem. 273, 8161– 8168 (1998).
Acknowledgements
I thank K. Beckingham, D. Bell-Pedersen and J. Braam for helpful suggestions, D. Hatton for assistance with the manuscript and figures, and Sheila Herman for preparation of Fig. 1. R.H.G. is an Investigator of the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Related links
Related links
DATABASE LINKS
FURTHER INFORMATION
Glossary
- TRACHEAE
-
The air tubes that form the respiratory system of an insect.
- MIDBLASTULA TRANSITION
-
Marks the initiation of zygotic gene transcription and the end of the embryo's dependency on maternal mRNA. The mid-blastula transition also marks a lengthening of the cell cycle.
- OLIGODENDROCYTE
-
A supporting cell in the nervous system that forms a myelin sheath around axons.
- SOMITE
-
A group of cells that breaks off from a column of mesoderm cells in a vertebrate embryo; the group then forms a segment of the backbone and associated structures.
- MYOBLAST
-
An embryonic cell that becomes a muscle cell or part of a muscle cell.
Rights and permissions
About this article
Cite this article
Gomer, R. Not being the wrong size. Nat Rev Mol Cell Biol 2, 48–55 (2001). https://doi.org/10.1038/35048058
Issue Date:
DOI: https://doi.org/10.1038/35048058
This article is cited by
-
An evolutionarily conserved protein CHORD regulates scaling of dendritic arbors with body size
Scientific Reports (2014)
-
Regulation of aggregate size and pattern by adenosine and caffeine in cellular slime molds
BMC Developmental Biology (2012)
-
A Dictyostelium chalone uses G proteins to regulate proliferation
BMC Biology (2009)
-
Dictyostelium cells bind a secreted autocrine factor that represses cell proliferation
BMC Biochemistry (2009)
-
Zac1 functions through TGFβIIto negatively regulate cell number in the developing retina
Neural Development (2007)