Changes in Cytoplasmic Volume Are Sufficient to Drive Spindle Scaling

Hazel, James W.; Krutkramelis, Kaspars; Mooney, Paul; Tomschik, Miroslav; Gerow, Kenneth G.; Oakey, John; Gatlin, Jesse C.

doi:10.1126/science.1243110

Cited by 180 publications

(220 citation statements)

References 30 publications

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“…Thus, the localization of SAFs by microtubules is sufficient to explain the observation that spindles assemble outside the peak of the Ran gradient in MUG cells. It has previously been shown that the size of the spindle is correlated with cell size during changes in early development (36)(37)(38)(39), between different species (39,40), between genetically different individuals within a species (40), and when spindles are assembled in vitro in cell extracts encapsulated in droplets (41,42). To our knowledge, the scaling of the spindle with cell size has not been investigated in human tissue culture cells such as were used in this study.…”

Section: Resultsmentioning

confidence: 92%

Spatial organization of the Ran pathway by microtubules in mitosis

Needleman

2016

Proc. Natl. Acad. Sci. U.S.A.

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Concentration gradients of soluble proteins are believed to be responsible for control of morphogenesis of subcellular systems, but the mechanisms that generate the spatial organization of these subcellular gradients remain poorly understood. Here, we use a newly developed multipoint fluorescence fluctuation spectroscopy technique to study the ras-related nuclear protein (Ran) pathway, which forms soluble gradients around chromosomes in mitosis and is thought to spatially regulate microtubule behaviors during spindle assembly. We found that the distribution of components of the Ran pathway that influence microtubule behaviors is determined by their interactions with microtubules, resulting in microtubule nucleators being localized by the microtubules whose formation they stimulate. Modeling and perturbation experiments show that this feedback makes the length of the spindle insensitive to the length scale of the Ran gradient, allows the spindle to assemble outside the peak of the Ran gradient, and explains the scaling of the spindle with cell size. Such feedback between soluble signaling pathways and the mechanics of the cytoskeleton may be a general feature of subcellular organization.RanGTP gradient | spatial organization | microtubule nucleation | feedback loop | spindle size C ells exhibit internal order over a range of length scales (1). The manners in which nanometer-sized proteins specify micrometer-scale subcellular organization remain poorly understood. Either mechanics or chemistry could in principle produce order at length scales of cellular dimensions. The simplest mechanical phenomena result from the cytoskeleton: Filaments can be microns long and thus their individual lengths may even be sufficient to specify large-scale subcellular organization. Chemical processes can produce large, defined length scales through the interplay between diffusion and reactions (2). The simplest reaction-diffusion phenomenon, which has been widely discussed in the context of subcellular organization, is a scenario in which a signaling molecule is phosphorylated at one location in a cell and diffuses away and gradually dephosphorylates (3). Simple mathematical models of such source-sink scenarios predict that the resulting steady-state profile will be an exponentially decreasing gradient of the phosphorylated form around the source, with a length scale of λ = ffiffiffiffiffiffiffiffi ffi D=k p , where D is the diffusion coefficient of the signaling molecule and k is the rate of dephosphorylation (3). λ is the average distance a molecule diffuses before it is dephosphorylated.Although mechanics and chemistry are individually sufficient to give rise to structure at micrometer-length scales, increasing evidence suggests that the joint contribution of both of them leads to novel phenomena that might be important for subcellular organization: The interactions of diffusible molecules with the cytoskeleton can alter their mobility and localization, greatly modifying reaction-diffusion processes (4-8); large-scale patterns can...

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Section: Resultsmentioning

confidence: 92%

Spatial organization of the Ran pathway by microtubules in mitosis

Needleman

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Most intriguingly, the spindle size scales linearly with the cell size up to a certain limit; and such a biphasic scaling relationship, as well as the critical cell size and spindle size for the biphasic transition, appear surprisingly consistent across metazoan species (5,8,10). Such size scaling is also partially reproduced in in vitro spindle reconstitution experiments (15,16). From the physics point of view, such universal size-scaling phenomena are highly significant, as they suggest intrinsic principles in the spatial organization of the mitotic spindle.…”

Section: Introductionmentioning

confidence: 77%

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Chen

Liu

2016

Biophysical Journal

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Chromosome segregation during mitosis hinges on proper assembly of the microtubule spindle that establishes bipolar attachment to each chromosome. Experiments demonstrate allometry of mitotic spindles and a universal scaling relationship between spindle size and cell size across metazoans, which indicates a conserved principle of spindle assembly at play during evolution. However, the nature of this principle is currently unknown. Researchers have focused on deriving the mechanistic underpinning of the size scaling from the mechanical aspects of the spindle assembly process. In this work we take a different standpoint and ask: What is the size scaling for? We address this question from the functional perspectives of spindle assembly checkpoint (SAC). SAC is the critical surveillance mechanism that prevents premature chromosome segregation in the presence of unattached or misattached chromosomes. The SAC signal gets silenced after and only after the last chromosome-spindle attachment in mitosis. We previously established a model that explains the robustness of SAC silencing based on spindle-mediated spatiotemporal regulation of SAC proteins. Here, we refine the previous model, and find that robust and timely SAC silencing entails proper size scaling of mitotic spindle. This finding provides, to our knowledge, a novel, function-oriented angle toward understanding the observed spindle allometry, and the universal scaling relationship between spindle size and cell size in metazoans. In a broad sense, the functional requirement of robust SAC silencing could have helped shape the spindle assembly mechanism in evolution.

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“…Remarkably, only duplicates related to cytoskeleton organization were retained under strong positive selection after both the a-and m-WGD events. With increased cell volume being one of the few constant alterations induced by polyploidy (Ramsey and Schemske, 2002), to what extent adaptive diversification of cytoskeleton genes may support the necessary scaling of intracellular structures after WGDs should be further examined (Hazel et al, 2013). The vast majority of retained duplicates in B. laevigata presented evidence of purifying selection, matching the hypothesis that dosage effects are crucial in maintaining functional traits after WGDs (Birchler and Veitia, 2012).…”

Section: Biased Genome Fractionation Over Timementioning

confidence: 86%

Repeated Whole-Genome Duplication, Karyotype Reshuffling, and Biased Retention of Stress-Responding Genes in Buckler Mustard

et al. 2015

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Whole-genome duplication (WGD) is usually followed by gene loss and karyotype repatterning. Despite evidence of new adaptive traits associated with WGD, the underpinnings and evolutionary significance of such genome fractionation remain elusive. Here, we use Buckler mustard (Biscutella laevigata) to infer processes that have driven the retention of duplicated genes after recurrent WGDs. In addition to the b-and a-WGD events shared by all Brassicaceae, cytogenetic and transcriptome analyses revealed two younger WGD events that occurred at times of environmental changes in the clade of Buckler mustard (Biscutelleae): a mesopolyploidy event from the late Miocene that was followed by considerable karyotype reshuffling and chromosome number reduction and a neopolyploidy event during the Pleistocene. Although a considerable number of the older duplicates presented signatures of retention under positive selection, the majority of retained duplicates arising from the younger mesopolyploidy WGD event matched predictions of the gene balance hypothesis and showed evidence of strong purifying selection as well as enrichment in gene categories responding to abiotic stressors. Retention of large stretches of chromosomes for both genomic copies supported the hypothesis that cycles of WGD and biased fractionation shaped the genome of this stress-tolerant polypolyloid, promoting the adaptive recruitment of stress-responding genes in the face of environmental challenges.

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Changes in Cytoplasmic Volume Are Sufficient to Drive Spindle Scaling

Cited by 180 publications

References 30 publications

Spatial organization of the Ran pathway by microtubules in mitosis

Spatial organization of the Ran pathway by microtubules in mitosis

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Repeated Whole-Genome Duplication, Karyotype Reshuffling, and Biased Retention of Stress-Responding Genes in Buckler Mustard

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