Mechanism of spindle pole organization and instability in human oocytes

So, Chi‐Chiu; Menelaou, Katerina; Uraji, Julia; Harasimov, Katarina; Steyer, Anna M.; Seres, K. Bianka; Bucevičius, Jonas; Lukinavičius, Gražvydas; Möbius, Wiebke; Sibold, Claus; Tandler-Schneider, Andreas; Eckel, H.; Moltrecht, Rüdiger; Blayney, Martyn; Elder, Kay; Schuh, Melina

doi:10.1126/science.abj3944

Cited by 81 publications

(77 citation statements)

References 138 publications

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“…This assisting role may explain why HSET levels contribute to controlling spindle length in a previously counterintuitive manner ( 37 ). Kinesin-14, however, also promotes pole focusing and bipolarization in cancer cells with too many centrosomes ( 38 , 39 ) and in meiotic oocytes lacking centrosomes ( 40 – 42 ), supporting the notion that its function can differ in a spindle region where microtubule minus ends are enriched, cooperating there with the minus motor dynein.…”

Section: Discussionmentioning

confidence: 74%

Cross-linker design determines microtubule network organization by opposing motors

Henkin

Chew

Nédélec

et al. 2022

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

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During cell division, cross-linking motors determine the architecture of the spindle, a dynamic microtubule network that segregates the chromosomes in eukaryotes. It is unclear how motors with opposite directionality coordinate to drive both contractile and extensile behaviors in the spindle. Particularly, the impact of different cross-linker designs on network self-organization is not understood, limiting our understanding of self-organizing structures in cells but also our ability to engineer new active materials. Here, we use experiment and theory to examine active microtubule networks driven by mixtures of motors with opposite directionality and different cross-linker design. We find that although the kinesin-14 HSET causes network contraction when dominant, it can also assist the opposing kinesin-5 KIF11 to generate extensile networks. This bifunctionality results from HSET’s asymmetric design, distinct from symmetric KIF11. These findings expand the set of rules underlying patterning of active microtubule assemblies and allow a better understanding of motor cooperation in the spindle.

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Section: Discussionmentioning

confidence: 74%

Cross-linker design determines microtubule network organization by opposing motors

Henkin

Chew

Nédélec

et al. 2022

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

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“…Finally, normal human oocytes are exceptional in exhibiting dramatic pole instability and chromosome separation defects relative to other mammalian oocytes, due at least in part to loss of expression of KIFC1/kinesin 14 (So et al, 2022). In C. elegans , loss of KLP-15/16/kinesin 14 does result in failed pole coalescence but does not result in pole stability defects like those observed in zyg-9 and tac-1 mutant oocytes (Chuang et al, 2020), and in normal human oocytes (So et al, 2022). While there appear to be both substantial similarities and differences in the requirements for oocyte meiotic spindle assembly in different species, higher spatial and temporal resolution studies of pole coalescence and spindle assembly dynamics in live control and mutant oocytes will likely reveal further conservation and divergence of mechanism.…”

Section: Discussionmentioning

confidence: 99%

C. elegans XMAP215/ZYG-9 and TACC/TAC-1 act at multiple times throughout oocyte meiotic spindle assembly to promote both the coalescence of pole foci into a bipolar structure, and the stability of coalesced poles, during oocyte meiotic cell division

Harvey

Bowerman

2022

Preprint

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The conserved two-component XMAP215/TACC modulator of microtubule stability is required in multiple animal phyla for acentrosomal spindle assembly during oocyte meiotic cell division, with C. elegans XMAP215/zyg-9 and TACC/tac-1 mutant oocytes exhibiting multiple and indistinguishable defects beginning early in meiosis I. To determine if these defects represent one or more early requirements with additional later and indirect consequences, or multiple temporally distinct and more direct requirements, we have used live cell imaging and fast-acting temperature-sensitive zyg-9 and tac-1 alleles to dissect at high temporal resolution their oocyte meiotic spindle assembly requirements. Our results from temperature upshift and downshift experiments indicate that the ZYG-9/TAC-1 complex has multiple temporally distinct and separable requirements throughout oocyte meiotic cell division. First, we show that during prometaphase ZYG-9 and TAC-1 promote the coalescence of early pole foci into a bipolar structure both by stabilizing pole foci as they grow and by limiting their growth rate, with these requirements being independent of an earlier defect in microtubule organization. Second, during metaphase, ZYG-9 and TAC-1 maintain spindle bipolarity by suppressing ectopic pole formation, and this pole stability is important for maintaining chromosome congression. Finally, we show that ZYG-9 and TAC-1 also are required for the proper coalescence of pole foci during meiosis II, independently of their requirements during meiosis I. Our findings highlight the value of fast-acting temperature-sensitive alleles for high resolution temporal dissection of gene requirements, and we discuss how negative regulation of microtubule stability by ZYG-9/TAC-1 during oocyte meiotic cell division might account for the observed defects in spindle pole coalescence and stability.

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“…This assisting role may explain why HSET levels contribute to controlling spindle length in a previously counter-intuitive manner 33 . Kinesin-14 however also promotes pole focusing and bipolarization in cancer cells with too many centrosomes 34,35 and in meiotic oocytes lacking centrosomes 36,37,38 , supporting the notion that its function can differ in a spindle region where microtubule minus ends are enriched, cooperating there with the minus motor dynein.…”

Section: Discussionmentioning

confidence: 62%

Crosslinker design determines microtubule network organization by opposing motors

Henkin

Chew

Nédélec

et al. 2022

Preprint

View full text Add to dashboard Cite

During cell division, crosslinking motors determine the architecture of the spindle, a dynamic microtubule network that segregates the chromosomes. It is unclear how motors with opposite directionality coordinate to drive both contractile and extensile behaviors in the spindle. Particularly, the impact of different crosslinker designs on network self-organization is not understood, limiting our understanding of self-organizing structures in cells, but also our ability to engineer new active materials. Here, we use experiment and theory to examine active microtubule networks driven by mixtures of motors with opposite directionality and different crosslinker design. We find that although the kinesin-14 HSET causes network contraction when dominant, it can also assist the opposing kinesin-5 KIF11 to generate extensile networks. This bifunctionality results from HSET’s asymmetric design, distinct from symmetric KIF11. These findings expand the set of rules underlying patterning of active microtubule assemblies and allow a better understanding of motor cooperation in the spindle.SIGNIFICANCE STATEMENTDuring cell division, the spindle apparatus segregates duplicated chromosomes for their inheritance by the daughter cells. The spindle is a highly interconnected network of microtubule filaments that are crosslinked by different types of molecular motors. How the different motors cooperate to organize the spindle network is not understood. Here, we show that an asymmetric crosslinker design can confer bifunctionality to a mitotic motor in the presence of other motors. The asymmetric motor supports both extensile and contractile microtubule network behaviors as observed in different parts of the spindle. These findings define new rules controlling the generation of active microtubule networks and allow us to better understand how motors cooperate to organize the correct spindle architecture when a cell divides.

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Mechanism of spindle pole organization and instability in human oocytes

Cited by 81 publications

References 138 publications

Cross-linker design determines microtubule network organization by opposing motors

Cross-linker design determines microtubule network organization by opposing motors

C. elegans XMAP215/ZYG-9 and TACC/TAC-1 act at multiple times throughout oocyte meiotic spindle assembly to promote both the coalescence of pole foci into a bipolar structure, and the stability of coalesced poles, during oocyte meiotic cell division

Crosslinker design determines microtubule network organization by opposing motors

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