Key Points
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The mitotic spindle is positioned with respect to asymmetries in cellular polarity to ensure that the partitioning of genomes is coordinated with the partitioning of developmental determinants.
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A small GTPase, CDC42, has a central role in establishing cell polarity and in promoting the localization of partitioning (PAR) proteins.
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Centrosomes nucleate the microtubule network in interphase and mitosis, and provide essential cues for specification of the anterior–posterior axis in development.
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Duplicated centrosomes are non-identical; the delivery of crucial components from one of the centrosomes to sites of polarized growth signals positional information to the mitotic spindle.
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Microtubule plus-ends are active sites for the interchange of information between regions of polarized growth and the centrosome.
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Proteins at microtubule plus-ends regulate microtubule dynamics as well as microtubule interactions with determinants of cell polarity.
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Microtubules that are pushing against the plasma membrane, or being pulled at plus-end capture sites, provide the motive force for spindle positioning. Cellular geometry and the generation of asymmetric forces impose constraints on these activities.
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Defects in spindle positioning are monitored by a signalling pathway (the spindle-positioning checkpoint) that functions to delay cytokinesis until proper spindle positioning is attained.
Abstract
Coordination between the asymmetric partitioning of cell-fate determinants and equal partitioning of genetic material is crucial to the generation of diverse cell types in a developing organism, and to the maintenance of genomic integrity. The emerging model is of a highly organized and dynamic cellular landscape, the form of which is defined by polarized signals within the cell. Cytoskeletal elements are necessary to generate this landscape and to provide motive forces for proper spindle positioning. These forces are generated by interactions between microtubules and the cell cortex.
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Acknowledgements
We thank J. C. Labbé, J. Deluca and B. Goldstein for their thoughtful and careful comments on this review. We also thank the reviewers for their helpful input. This work was supported by the National Institutes of Heath.
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Glossary
- CENTROSOME
-
Also called the microtubule-organizing centre (MTOC) or spindle pole, this structure nucleates microtubules and is important for signalling processes.
- SPINDLE
-
A bipolar microtubule array with microtubules organized from each spindle pole. The spindle is composed of polar, kinetochore and astral microtubules.
- ANAPHASE
-
The period of mitosis during which duplicated chromosomes are segregated. In anaphase A, chromosomes move towards centrosomes; in anaphase B, the centrosomes are segregated.
- CYTOKINESIS
-
The separation of a cell into two, marked by ingression of the cleavage 'furrow' between two segregated masses of genomic DNA.
- SMALL GTPases
-
Diverse cellular regulatory proteins that are controlled by the nature of bound nucleotide (active when bound to GTP; inactive when bound to GDP).
- TIGHT JUNCTION
-
A seal between adjacent epithelial cells, just beneath their apical surface. PAR proteins migrate to tight junctions in mammalian cells.
- MICROTUBULE-ORGANIZING CENTRE
-
(MTOC). Also called the centrosome or spindle-pole body, this structure nucleates and organizes microtubules.
- P1
-
The first cell division in C. elegans produces a large anterior blastemere, AB, a blastomere and a smaller posterior blastomere, P1.
- SPINDLE-POLE BODY
-
The budding-yeast equivalent of the centrosome/spindle pole or MTOC. This structure, which is embedded in the nuclear envelope, nucleates both cytoplasmic and nuclear microtubules.
- ASTER
-
An organized microtubule array, with the microtubule minus-ends focused at a point or centrosome, and the plus-ends emanating outwards.
- CHROMATIN
-
Chromosomal DNA and associated proteins.
- PLUS-END
-
The predominantly dynamic end of a microtubule, with β-tubulin exposed.
- METAZOAN
-
Refers to the kingdom Animalia (animals) that comprises roughly 35 phyla of multicellular organisms.
- CENTRIOLE
-
A short, barrel-like array of microtubules that organizes the centrosome and contributes to cytokinesis and cell-cycle progression.
- TUBULIN
-
The basic subunit of microtubules. Tubulin comes in two forms, α- and β-tubulin, which form heterodimers that make up microtubules.
- GTPase-ACTIVATING PROTEIN
-
(GAP). A protein that inactivates small GTP-binding proteins, such as RAS-family members, by increasing their rate of GTP hydrolysis.
- ADENOMATOUS POLYPOSIS COLI
-
(APC). A protein that is mutated in many colorectal cancers. APC binds to microtubules and the microtubule regulator EB1.
- CYCLINS
-
A family of binding partners for the main cell-cycle regulators, cyclin-dependent kinases. Cyclins are completely degraded and newly synthesized for progression through each cell cycle.
- MINUS-END
-
The predominantly stable end of a microtubule, which has exposed α-tubulin.
- KINETOCHORE
-
A protein complex that provides a link between centromeric DNA and microtubules.
- KARYOGAMY
-
The process in which two haploid nuclei come together and fuse to form a diploid nucleus during mating in S. cerevisiae.
- CATASTROPHE
-
The transition from microtubule growth to shortening.
- PROTOFILAMENT
-
Tubulin dimers aligned end-to-end make up protofilaments. Several protofilaments (usually 13) are organized into a tubular structure to form microtubules.
- ASTRAL MICROTUBULE
-
A microtubule that is nucleated at the spindle pole and grows outwards towards the cell cortex; it is involved in spindle positioning.
- FORMINS
-
A family of proteins that contain a formin homology-2 (FH2) domain. They are capable of promoting actin assembly.
- RNA INTERFERENCE
-
(RNAi). A method to block the translation of RNA and thereby 'knock-down' the levels of specific proteins.
- GUANINE NUCLEOTIDE-DISSOCIATION INHIBITOR
-
(GDI). A protein that inhibits the dissociation of GDP and therefore its replacement by GTP in a small GTPase, thereby maintaining the GTPase in an inactive state.
- N-MYRISTOYLATION
-
The chemical addition of the fatty acid myristate to the amino terminus of a protein, which enables that protein to become localized to a membrane.
- PLECKSTRIN-HOMOLOGY DOMAIN
-
A protein domain that is typically made up of 100 amino-acid residues, and is found in many proteins that are involved in intracellular signalling. Named after pleckstrin, the main substrate of protein kinase C in platelets.
- METAPHASE PLATE
-
During mitosis, chromosomes align at an equatorial plane between the two spindle poles, which is defined as the metaphase plate.
- MITOTIC EXIT NETWORK
-
(MEN). A signalling cascade that regulates the timing of spindle disassembly and cytokinesis.
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Pearson, C., Bloom, K. Dynamic Microtubules Lead the Way for Spindle Positioning. Nat Rev Mol Cell Biol 5, 481–492 (2004). https://doi.org/10.1038/nrm1402
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DOI: https://doi.org/10.1038/nrm1402
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