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Chromosome movement in mitosis requires microtubule anchorage at spindle poles.

Gordon MB, Howard L, Compton DA - J. Cell Biol. (2001)

Bottom Line: Perturbation of NuMA alone disrupts spindle pole organization and delays anaphase onset, but does not alter the velocity of oscillatory chromosome movement in prometaphase.Perturbation of HSET alone increases the duration of prometaphase, but does not alter the velocity of chromosome movement in prometaphase or anaphase.These results demonstrate that anchorage of microtubule minus ends at spindle poles mediated by overlapping mechanisms involving both NuMA and HSET is essential for chromosome movement during mitosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

ABSTRACT
Anchorage of microtubule minus ends at spindle poles has been proposed to bear the load of poleward forces exerted by kinetochore-associated motors so that chromosomes move toward the poles rather than the poles toward the chromosomes. To test this hypothesis, we monitored chromosome movement during mitosis after perturbation of nuclear mitotic apparatus protein (NuMA) and the human homologue of the KIN C motor family (HSET), two noncentrosomal proteins involved in spindle pole organization in animal cells. Perturbation of NuMA alone disrupts spindle pole organization and delays anaphase onset, but does not alter the velocity of oscillatory chromosome movement in prometaphase. Perturbation of HSET alone increases the duration of prometaphase, but does not alter the velocity of chromosome movement in prometaphase or anaphase. In contrast, simultaneous perturbation of both HSET and NuMA severely suppresses directed chromosome movement in prometaphase. Chromosomes coalesce near the center of these cells on bi-oriented spindles that lack organized poles. Immunofluorescence and electron microscopy verify microtubule attachment to sister kinetochores, but this attachment fails to generate proper tension across sister kinetochores. These results demonstrate that anchorage of microtubule minus ends at spindle poles mediated by overlapping mechanisms involving both NuMA and HSET is essential for chromosome movement during mitosis.

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Models for the NuMA- and HSET-dependent anchorage of microtubules at spindle poles. (A) The matrix model posits that NuMA and an unidentified matrix element associated with HSET anchor microtubule ends at spindle poles. This anchorage creates drag on microtubules that provides the necessary resistance for forces generated by kinetochore-associated motors (large solid arrows) to create chromosome movement. (B) The microtubule cross-linking model posits that the cross-linking and minus end–directed motility (small arrows) of HSET and NuMA (in association with dynein) involved in focusing microtubules at spindle poles also creates physical linkages between kinetochore and nonkinetochore microtubules. This connects microtubules involved in poleward forces (large solid arrows) with microtubules involved in polar ejection forces (large open arrows), as well as interdigitating microtubules emanating from opposite poles, which constrains the positions of the spindle poles and permits chromosomes to move relative to the poles.
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Figure 8: Models for the NuMA- and HSET-dependent anchorage of microtubules at spindle poles. (A) The matrix model posits that NuMA and an unidentified matrix element associated with HSET anchor microtubule ends at spindle poles. This anchorage creates drag on microtubules that provides the necessary resistance for forces generated by kinetochore-associated motors (large solid arrows) to create chromosome movement. (B) The microtubule cross-linking model posits that the cross-linking and minus end–directed motility (small arrows) of HSET and NuMA (in association with dynein) involved in focusing microtubules at spindle poles also creates physical linkages between kinetochore and nonkinetochore microtubules. This connects microtubules involved in poleward forces (large solid arrows) with microtubules involved in polar ejection forces (large open arrows), as well as interdigitating microtubules emanating from opposite poles, which constrains the positions of the spindle poles and permits chromosomes to move relative to the poles.

Mentions: Two models are most plausible to explain how microtubule anchorage at spindle poles contributes to chromosome movement, and both of these ideas have been proposed previously in alternate forms. One model involves the anchorage of microtubule minus ends in a matrix (McIntosh 1980; Pickett-Heaps et al. 1982; Rebhun and Palazzo 1988; Nicklas 1989). This matrix would bind to microtubules and hold the minus ends so that poleward forces generated at kinetochores would cause chromosomes to move relative to the poles rather than the poles relative to the chromosomes (Fig. 8 A). If the interaction between this matrix and microtubules were disrupted, then the drag the matrix imposes on microtubules would be relieved and chromosome movement would stall due to the lack of resistance on kinetochore microtubules.


Chromosome movement in mitosis requires microtubule anchorage at spindle poles.

Gordon MB, Howard L, Compton DA - J. Cell Biol. (2001)

Models for the NuMA- and HSET-dependent anchorage of microtubules at spindle poles. (A) The matrix model posits that NuMA and an unidentified matrix element associated with HSET anchor microtubule ends at spindle poles. This anchorage creates drag on microtubules that provides the necessary resistance for forces generated by kinetochore-associated motors (large solid arrows) to create chromosome movement. (B) The microtubule cross-linking model posits that the cross-linking and minus end–directed motility (small arrows) of HSET and NuMA (in association with dynein) involved in focusing microtubules at spindle poles also creates physical linkages between kinetochore and nonkinetochore microtubules. This connects microtubules involved in poleward forces (large solid arrows) with microtubules involved in polar ejection forces (large open arrows), as well as interdigitating microtubules emanating from opposite poles, which constrains the positions of the spindle poles and permits chromosomes to move relative to the poles.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196006&req=5

Figure 8: Models for the NuMA- and HSET-dependent anchorage of microtubules at spindle poles. (A) The matrix model posits that NuMA and an unidentified matrix element associated with HSET anchor microtubule ends at spindle poles. This anchorage creates drag on microtubules that provides the necessary resistance for forces generated by kinetochore-associated motors (large solid arrows) to create chromosome movement. (B) The microtubule cross-linking model posits that the cross-linking and minus end–directed motility (small arrows) of HSET and NuMA (in association with dynein) involved in focusing microtubules at spindle poles also creates physical linkages between kinetochore and nonkinetochore microtubules. This connects microtubules involved in poleward forces (large solid arrows) with microtubules involved in polar ejection forces (large open arrows), as well as interdigitating microtubules emanating from opposite poles, which constrains the positions of the spindle poles and permits chromosomes to move relative to the poles.
Mentions: Two models are most plausible to explain how microtubule anchorage at spindle poles contributes to chromosome movement, and both of these ideas have been proposed previously in alternate forms. One model involves the anchorage of microtubule minus ends in a matrix (McIntosh 1980; Pickett-Heaps et al. 1982; Rebhun and Palazzo 1988; Nicklas 1989). This matrix would bind to microtubules and hold the minus ends so that poleward forces generated at kinetochores would cause chromosomes to move relative to the poles rather than the poles relative to the chromosomes (Fig. 8 A). If the interaction between this matrix and microtubules were disrupted, then the drag the matrix imposes on microtubules would be relieved and chromosome movement would stall due to the lack of resistance on kinetochore microtubules.

Bottom Line: Perturbation of NuMA alone disrupts spindle pole organization and delays anaphase onset, but does not alter the velocity of oscillatory chromosome movement in prometaphase.Perturbation of HSET alone increases the duration of prometaphase, but does not alter the velocity of chromosome movement in prometaphase or anaphase.These results demonstrate that anchorage of microtubule minus ends at spindle poles mediated by overlapping mechanisms involving both NuMA and HSET is essential for chromosome movement during mitosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

ABSTRACT
Anchorage of microtubule minus ends at spindle poles has been proposed to bear the load of poleward forces exerted by kinetochore-associated motors so that chromosomes move toward the poles rather than the poles toward the chromosomes. To test this hypothesis, we monitored chromosome movement during mitosis after perturbation of nuclear mitotic apparatus protein (NuMA) and the human homologue of the KIN C motor family (HSET), two noncentrosomal proteins involved in spindle pole organization in animal cells. Perturbation of NuMA alone disrupts spindle pole organization and delays anaphase onset, but does not alter the velocity of oscillatory chromosome movement in prometaphase. Perturbation of HSET alone increases the duration of prometaphase, but does not alter the velocity of chromosome movement in prometaphase or anaphase. In contrast, simultaneous perturbation of both HSET and NuMA severely suppresses directed chromosome movement in prometaphase. Chromosomes coalesce near the center of these cells on bi-oriented spindles that lack organized poles. Immunofluorescence and electron microscopy verify microtubule attachment to sister kinetochores, but this attachment fails to generate proper tension across sister kinetochores. These results demonstrate that anchorage of microtubule minus ends at spindle poles mediated by overlapping mechanisms involving both NuMA and HSET is essential for chromosome movement during mitosis.

Show MeSH
Related in: MedlinePlus