Q J Med 2002; 95: 709-710
© 2002 Association of Physicians
Biologic |
Minnie mice
In determining the size of an animal or plant, it has long been thought that size itself is in some way measured and monitored. Experimental manipulation of rates of cell proliferation or cell size during growth results in organs and/or organisms of the normal size that may consist of fewer larger cells, or more numerous smaller cells.1 As Day and Lawrence2 have pointed out, when looking for answers to questions about how this is achieved, the intuitive response is to search for mechanisms that count cell divisions or add up cell numbers.
Ploidy is clearly one important factor, and for a given cell type, cell size is usually proportional to ploidy. The ploidy of newts and salamanders can be manipulated to produce animals with chromosome complements ranging from haploid to pentaploid, but although these newts have different cell numbers, they have the same total amount of DNA. Mature tetraploid salamanders (Amblystoma mexicanum) closely resemble their diploid counterparts despite having half the number of cells. Tetraploid mice also compensate for the larger size of their cells by a reduction in cell number. Tetraploid fetuses are about 85% the size of their stage matched diploid fellows but have about 40% as many cells—most of these animals die.
These cell-number reduction mechanisms seem not to operate in mammals after birth. Knockout mice that lack p27Kip (a cyclin-associated kinase inhibitor that controls entry into S) are born normally sized, but subsequently grow considerably larger than littermates, with no decrease in cell size. Day and Lawrence2 suggest that these effects of polyploidy indicate that animals measure dimensions rather than cell number.
Morphogens may be important in the local aspect of the process of development of a particular size. A morphogen is a soluble molecule, capable of short and long-range signalling, that specifies different cell fates at different concentrations. Theoretically, a concentration gradient of a morphogen from its source to the site of degradation can specify several different fates at different concentration levels, thereby establishing pattern.3 Thus ‘positional information’ is provided by concentrations of chemical morphogens that act across small fields of embryonic cells (
30–50 cells per field). It is known that morphogen gradients are clearly significant in the ‘local’ process of size determination as changes in the pattern or level of Dpp and Wnt production can redesign and affect the dimensions of the Drosophila wing.
Day and Lawrence2 suggest that the end points of a gradient of morphogen—the highest and lowest concentrations—should be regarded as fixed. Individual cells, or local groups of cells, monitor the declivity of the gradient and grow and divide for as long as the slope is sufficiently steep. Growth anywhere in the field of cells expands the gradient and so reduces the slope; eventually, in each region of the field, the local value falls below a threshold and cell proliferation ceases. It is important to note that the slope may be restored by an increase in the frequency of apoptosis. Some morphogens are internalized by cells in their field and may be degraded or re-exported, and since a certain amount is lost with each cell passage, cell number may affect the morphogen gradient directly.
Eventually, in each region of the field, the local level falls below a threshold and cell proliferation ceases. If the slope becomes too gentle, there will be no net growth. As the decision whether to grow, divide or enter apoptosis must be made at the level of each cell, there must be a mechanism to convey information about the size of the relevant compartment to individual cells.
This lengthy preamble sets the scene for an astonishing paper by Settleman's group.4 They have produced what appear to be mini-mice (around two-thirds of the normal size at birth) with cells that appear to be about two-thirds the normal size. In mice engineered to be Rho-GAP-deficient, cells are smaller, the authors believe, by an effect on part of the insulin-signalling pathway (Rho-GAPases mediate signalling pathways that regulate a lot of things, including organization of the cellular cytoskeleton and cell cycle progression).
In general, most genetically determined failures of growth act via the growth hormone/insulin-like-growth factor pathway. GH exerts insulin-like effects acutely, increasing glucose uptake in muscle and fat, stimulating amino acid uptake and protein synthesis in the liver and muscle, and inhibiting lipolysis in adipose tissue. Insulin growth factors 1 and 2 (IGF1, IGF2) and their specific receptors and growth hormone receptor (GHr) may all modify growth in appropriately manipulated mice. IGF1 disruption produces embryonic growth retardation and poor post-natal growth; disruption of IGF2 produces normally proportioned animals of around half the normal adult body weight. However, the unusual pigmy phenotype arises from inactivation of a gene called Hmgi-c (high mobility group DNA binding protein). These proteins produced by this gene family organize the nuclear scaffold, and are important in the assembly of steriospecific transcriptional complexes—the gene products allow DNA to bend though large angles on binding.5 The gene acts by reducing growth in a uniform manner via a cell-autonomous reduction in the rate of cell division—homozygote pigmy mice have body weights of about 40% and heterozygotes about 80% of wild-type littermates. The gene is expressed at high levels in all tissues except brain during normal development and it is fascinating to note that pigmy mice brain weights are normal. Fat cells appear to be affected more than other types and lipomas are common in these animals.
The paper of Sordella et al. suggests that activity of the RHO GTPase modulates a signal from insulin/IGFs to CREB determining cell and animal size during embryogenesis. Perhaps this indicates a ‘cell level’ determination of size via cytoskeletal activity. I have to say this would surprise me, but I am not sure why.
References
1. Berry CL, Slocombe GW, et al. The effects of damage to the renal tubular cell population in growing rats. J Pathol1978; 125:193–200.[Medline]
2. Day SJ, Lawrence PA. Measuring dimensions: the regulation of size and shape. Development2000; 127:2977–87.[Abstract]
3. Wolpert L. Positional information and pattern formation in development. Dev Genetics1994; 15:485–90.[Medline]
4. Sordella R, Classon M, et al. Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development. Dev Cell2002; 2:553–65.[Web of Science][Medline]
5. Zhou X, Benson KF, Ashar HR, Chada K. Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature1995; 376:771–4.[Medline]
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