Intracellular Scaling Mechanisms

Abstract

Organelle function is often directly related to organelle size. However, it is not necessarily absolute size but the organelle-to-cell-size ratio that is critical. Larger cells generally have increased metabolic demands, must segregate DNA over larger distances, and require larger cytokinetic rings to divide. Thus, organelles often must scale to the size of the cell. The need for scaling is particularly acute during early development during which cell size can change rapidly. Here, we highlight scaling mechanisms for cellular structures as diverse as centrosomes, nuclei, and the mitotic spindle, and distinguish them from more general mechanisms of size control. In some cases, scaling is a consequence of the underlying mechanism of organelle size control. In others, size-control mechanisms are not obviously related to cell size, implying that scaling results indirectly from cell-size-dependent regulation of size-control mechanisms.

Figure 1.

Molecular rulers. (A) In its simplest form, a molecular ruler provides a structural scaffold templating the size of the target organelle. (B) Bacteriophage λ tail length is set by the product of gene H. Tail length correlates with protein length (i.e., number of amino acids). (C) Decapentaplegic (Dpp) gradients scale with tissue size of imaginal discs during Drosophila development. (Adapted from data in Wartlick et al. 2011.) (D) Centrosome size sets mitotic spindle length by controlling the length scale of a TPX2 gradient along spindle microtubules (Greenan et al. 2010).

Figure 2.

Direct cell-boundary sensing. (A) Fertilized one- and two-cell stage embryos of Xenopus laevis with microtubules labeled in green and DNA in red. (Image courtesy of Martin Wühr, Harvard Medical School.) Microtubules nucleated from centrosomes expand until they reach the cell boundary, completely filling the cell (insets show schematic representation of astral microtubules). (B) The structural components of the contractile ring, actin, and myosin II assemble directly on the plasma membrane. Thus, the initial size of the ring exactly matches cell diameter. In Caenorhabditis elegans, the number of actomyosin “contractile units” (CU) is dependent on initial ring size and is maintained throughout the constriction process. Constriction rate is set by CU number, ensuring constriction rate scales with initial ring size, and, thus, cytokinesis completes in the same amount of time regardless of initial cell size (Carvalho et al. 2009). (C) In the fission yeast Schizosaccharomyces pombe, a gradient of the cell polarity protein kinase Pom1 directs the positioning of contractile-ring assembly and subsequent cell division. Pom1 inhibits the kinase Cdr2 in a dose-dependent manner. Because of a constant gradient length, as cells elongate, Pom1 levels decrease at the cell middle, eventually allowing cytokinesis to proceed (Moseley et al. 2009).

Figure 3.

Assembly rates and dynamic balance. (A) “Antennae model” for microtubule length control, in which accumulation of kinesin-8 leads to length dependent microtubule depolymerization (Varga et al. 2006). (B) A dynamic balance model combining length-dependent disassembly (as in A) and a length-independent assembly leading to a single stably defined steady-state microtubule length. (C) Nuclear growth in early Xenopus embryos is limited by available importin α levels, which are reduced in smaller cells (see D). (D) For spherical cells of radius, R, surface area to volume ratio (SA/V) is inversely related to cell size. In small cells, increased SA/V results in greater sequestration of importin α to the membrane from the cytoplasm, resulting in a reduction in the concentration of free importin α. (E) “Timer model”: A structure that undergoes assembly faster (red) will end up larger than a structure that assembles more slowly (blue) in a given time interval.

Figure 4.

Limiting pools. (A) In a simple limiting pool model, a cell has a fixed amount of an essential structural molecule, the limiting component. Once this component is used up, organelle growth ceases. As long as cells begin with a starting amount of the limiting component that is proportional to cell volume, organelle size will scale with cell size. (B) Limiting pools can also work with a dynamic balance model. Organelle growth depletes the cytoplasm of an essential component, thereby reducing the rate of assembly. This depletion of the component will be greater as a function of organelle size in small cells compared with large cells, which start with a larger overall pool. Thus, for a given organelle size (dashed vertical line), the assembly rate in the larger cell is higher than that for the smaller cell. Steady-state size is given by the point at which the rate of disassembly (gray line) exactly matches the assembly rate (intersections marked by circles). Note that this will occur at a larger size for larger cells. (C) A schematic of how limiting amounts of centrosome material set centrosome size in C. elegans embryos (Decker et al. 2011). The total amount of the limiting component is set by the amount of maternally provided cytoplasm in the oocyte, which is then partitioned into cells as a function of cell volume as cells divide. (D) A limiting pool model predicts that the combined total volume of all organelles should be independent of the organelle number. Consequently, for C. elegans, the total volume of the eight centrosomes in the four-cell-stage embryo is equal to the volume of the two centrosomes in the one-cell embryo. Similarly, mutants that differ in centrosome number show corresponding changes in centrosome volume, again such that total volume is constant.