Spindle and Chromosome Motility
The discovery of microtubule motor proteins with a clear involvement in mitosis and meiosis has attracted great interest, since motor proteins could account for many of the movements of the spindle and chromosomes in dividing cells. Microtubule motors bind to and move unidirectionally on microtubules and have been proposed to generate the force required for spindle assembly and maintenance, attachment of the chromosomes to the spindle, and movement of chromosomes toward opposite poles. Kinesin motors have been shown necessary for establishing spindle bipolarity, positioning chromosomes on the metaphase plate, and maintaining forces in the spindle. Evidence also exists that kinesin motors can facilitate microtubule depolymerization, raising the possibility that the motors modulate microtubule dynamics during mitosis. The force generated by microtubule polymerization/depolymerization is thought to contribute to, or underlie, spindle dynamics and movements of the chromosomes.
Many of the newly identified kinesin-related proteins (KRPs) localize to the spindle in mitotically dividing cells and are implicated in spindle function by both their cellular localization and mutant effects. The Kinesin-5 (formerly BimC) subfamily kinesins function in centrosome or spindle pole body separation, necessary for bipolar spindle assembly. Mutants arrest with monopolar spindles and highly polyploid cells caused by duplication of chromosomes followed by failure of normal spindles to form and segregate chromosomes. Xklp2, a spindle-associated kinesin in Xenopus, is associated with spindle poles and centrosomes, and required for centrosome separation and spindle assembly in in vitro assays, but appears to have a different role in centrosome separation than the Kinesin-5 motors. Xklp2 is divergent in sequence compared to the Kinesin-5 proteins, and thereby constitutes a different class of kinesins.
Ncd, a minus end-directed meiotic kinesin in Drosophila that also functions in early mitosis, is localized to spindles in oocytes and has been proposed to perform a spindle pole function in meiosis, organizing the ends of spindle microtubules into poles. Mutant oocytes show highly abnormal multipolar spindles, or spindles with diffuse poles, consistent with this hypothesis. Other Kinesin-14 (formerly C-terminal motor) kinesins, several of which have also been shown to be minus-end motors, may perform similar roles in spindle pole function in other organisms. Klp3A, another Drosophila meiotic kinesin, localizes to the midbody of spermatocyte spindles, and is thought to perform a role in cytokinesis.
MKLP1 and CHO1, members of the Kinesin-6 (formerly MKLP1) group, are present in the spindle midbody during telophase and have been hypothesized to mediate the sliding of spindle fibers in the later stages of anaphase that are needed for spindle elongation and separation of the chromosomes. MKLP1 has been demonstrated to be a plus-end kinesin motor and could move toward plus ends of antiparallel spindle microtubules, pushing them apart.
Remarkably, several KRPs have been demonstrated to be chromosome-associated, providing a direct link between the chromosomes and microtubules of the spindle. CENP-E, a member of the Kinesin-7 (formerly CENP-E) group and MCAK, a member of the Kinesin-13 (formerly MCAK/KIF2) group have both been shown to be kinetochore kinesin proteins, but localize to different regions of the kinetochore. These kinesins are therefore likely to perform distinct roles in mitotic chromosome movement, a hypothesis supported by their divergent sequences. Evidence has been reported that CENP-E is a plus-end microtubule motor with a role in chromosome congression to the plate in prometaphase. The Kinesin-13 subfamily includes not only MCAK, but also XKCM1, a centromere-associated Xenopus kinesin, which appears to be required for establishing and maintaining mitotic spindles. Immunodepletion of XKCM1 causes the formation of abnormally long microtubules in in vitro assays, which can be suppressed by addition of purified XKCM1. These findings implicate XKCM1 in destabilization of microtubules which could play a role during spindle assembly. XKCM1 has also been proposed to function in destabilization of microtubules at the kinetochore, driving poleward and away-from-the-pole chromosome movement. The significance of these proposed roles of XKCM1 in vivo remains to be established.
Kinesin proteins that associate with chromosomes along the length of their arms have recently been reported and named Kinesin-4 (formerly Chromokinesin or KIF4) motors. Xklp1, a chromokinesin of Xenopus, is required for maintenance of spindle bipolarity and congression of chromosomes to the metaphase plate. Nod, a meiotic kinesin in Drosophila , has been postulated to perform an analogous role in oocyte meiosis of positioning chromosomes on the metaphase plate.
The demonstration of kinesin motor protein function in spindle and chromosome motility represents a major step forward in understanding the basis of cell division. Still to be illuminated are the cellular roles of many of the kinesin proteins, the interactions of the proteins with one another and with components of the mitotic / meiotic apparatus, and the regulation of the kinesin proteins in the cell cycle.
Contributed by Sharyn Endow
- Walczak, C.E. & Mitchison, T. (1996) Cell 85:943-946
- Vernos, I. & Karsenti, E. (1996) Curr. Opin. Cell Biol. 8:4-9
- Sawin, K.E. & Endow, S.A. (1993) BioEssays 15:399-407
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Created 7 July 1996 20:00 GMT
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