Microtubule re-organization during female meiosis in C elegans
- Technische Universitaet Dresden, Germany
- University of California, Santa Barbara, United States
- University of Virginia, United States
- Zuse Institute Berlin, Germany
- University of Alberta, Canada
- Flatiron Institute, United States
Abstract
The female meiotic spindles of most animals are acentrosomal and undergo striking morphological changes while transitioning from metaphase to anaphase. The ultra-structure of acentrosomal spindles, and how changes to this structure correlate with such dramatic spindle rearrangements remains largely unknown. To address this, we applied light microscopy, large-scale electron tomography and mathematical modeling of female meiotic C. elegans spindles undergoing the transition from metaphase to anaphase. Combining these approaches, we find that meiotic spindles are dynamic arrays of short microtubules that turn over on second time scales. The results show that the transition from metaphase to anaphase correlates with an increase in the number of microtubules and a decrease in their average length. Detailed analysis of the tomographic data revealed that the length of microtubules changes significantly during the metaphase-to-anaphase transition. This effect is most pronounced for those microtubules located within 150 nm of the chromosome surface. To understand the mechanisms that drive this transition, we developed a mathematical model for the microtubule length distribution that considers microtubule growth, catastrophe, and severing. Using Bayesian inference to compare model predictions and data, we find that microtubule turn-over is the major driver of the observed large-scale reorganizations. Our data suggest that in metaphase only a minor fraction of microtubules, those that are closest to the chromosomes, are severed. The large majority of microtubules, which are not in close contact with chromosomes, do not undergo severing. Instead, their length distribution is fully explained by growth and catastrophe alone. In anaphase, even microtubules close to the chromosomes show no signs of cutting. This suggests that the most prominent drivers of spindle rearrangements from metaphase to anaphase are changes in nucleation and catastrophe rate. In addition, we provide evidence that microtubule severing is dependent on the presence of katanin.
Data availability
Electron microscopy models of microtubules and chromosome surfaces will be made available on Dryad under doi.org/10.5061/dryad.x3ffbg7k5. Example data and analysis code is available at https://github.com/SebastianFuerthauer/SpindleRerrangement
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C. elegans meiotic spindlesDryad Digital Repository, doi.org/10.5061/dryad.x3ffbg7k5.
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Meiosis I spindles of Metaphase, early Anaphase and Anaphasehttps://www.cell.com/current-biology/fulltext/S0960-9822(18)30911-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982218309114%3Fshowall%3Dtrue.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (MU 1423/3-1)
- Ina Lantzsch
Deutsche Forschungsgemeinschaft (MU 1423/3-2)
- Ina Lantzsch
Deutsche Forschungsgemeinschaft (MU 1423/8-1)
- Erik Szentgyoergyi
Technische Universität Darmstadt (Frauenhabilitation)
- Stefanie Redemann
Natural Sciences and Engineering Research Council of Canada
- Martin Srayko
National Science Foundation (DMR-0820484)
- Che-Hang Yu
National Science Foundation (NeuroNex #1934288)
- Che-Hang Yu
National Institutes of Health (1R01GM104976-01)
- Che-Hang Yu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Lantzsch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Microtubule re-organization during female meiosis in C elegans
eLife 10:e58903.
https://doi.org/10.7554/eLife.58903
Further reading
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- Cell Biology
Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
