Mechanics of spindle orientation in human mitotic cells is determined by pulling forces on astral microtubules and clustering of cortical dynein

Maya I Anjur-Dietrich¹, Vicente Gomez Hererra², Reza Farhadifar³, Haiyin Wu⁴, Holly Merta⁵, Shirin Bahmanyar⁵, Michael J Shelley⁶, Daniel J Needleman⁷

Affiliations

¹ School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA. Electronic address: mayaiad@mit.edu.
² Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA.
³ Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.
⁴ Department of Physics, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
⁵ Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.
⁶ Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA; Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.
⁷ School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.

PMID: 38866013
DOI: 10.1016/j.devcel.2024.05.022

Free article

Mechanics of spindle orientation in human mitotic cells is determined by pulling forces on astral microtubules and clustering of cortical dynein

Maya I Anjur-Dietrich et al. Dev Cell. 2024.

Free article

. 2024 Sep 23;59(18):2429-2442.e4.

doi: 10.1016/j.devcel.2024.05.022. Epub 2024 Jun 11.

Authors

Maya I Anjur-Dietrich¹, Vicente Gomez Hererra², Reza Farhadifar³, Haiyin Wu⁴, Holly Merta⁵, Shirin Bahmanyar⁵, Michael J Shelley⁶, Daniel J Needleman⁷

Affiliations

¹ School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA. Electronic address: mayaiad@mit.edu.
² Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA.
³ Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.
⁴ Department of Physics, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
⁵ Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.
⁶ Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA; Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.
⁷ School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.

PMID: 38866013
DOI: 10.1016/j.devcel.2024.05.022

Abstract

The forces that orient the spindle in human cells remain poorly understood due to a lack of direct mechanical measurements in mammalian systems. We use magnetic tweezers to measure the force on human mitotic spindles. Combining the spindle's measured resistance to rotation, the speed at which it rotates after laser ablating astral microtubules, and estimates of the number of ablated microtubules reveals that each microtubule contacting the cell cortex is subject to ∼5 pN of pulling force, suggesting that each is pulled on by an individual dynein motor. We find that the concentration of dynein at the cell cortex and extent of dynein clustering are key determinants of the spindle's resistance to rotation, with little contribution from cytoplasmic viscosity, which we explain using a biophysically based mathematical model. This work reveals how pulling forces on astral microtubules determine the mechanics of spindle orientation and demonstrates the central role of cortical dynein clustering.

Keywords: clustering; dynein; forces; mechanics; metaphase; microtubules; mitosis; orientation; spindle.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Clustering of cortical dynein regulates the mechanics of spindle orientation in human mitotic cells.
Anjur-Dietrich MI, Hererra VG, Farhadifar R, Wu H, Merta H, Bahmanyar S, Shelley MJ, Needleman DJ. Anjur-Dietrich MI, et al. bioRxiv [Preprint]. 2023 Sep 12:2023.09.11.557210. doi: 10.1101/2023.09.11.557210. bioRxiv. 2023. Update in: Dev Cell. 2024 Sep 23;59(18):2429-2442.e4. doi: 10.1016/j.devcel.2024.05.022. PMID: 37745442 Free PMC article. Updated. Preprint.

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Mechanics of spindle orientation in human mitotic cells is determined by pulling forces on astral microtubules and clustering of cortical dynein

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Mechanics of spindle orientation in human mitotic cells is determined by pulling forces on astral microtubules and clustering of cortical dynein

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