Remote control of microtubule plus-end dynamics and function from the minus-end

Chen, Xiuzhen; Widmer, Lukas A.; Stangier, Marcel; Steinmetz, Michel O.; Stelling, Jörg; Barral, Yves

doi:10.7554/elife.48627

Cited by 27 publications

(42 citation statements)

References 66 publications

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“…Interestingly, biased MTOC activity in neuroblasts disappears during mitosis when the mother centriole-containing centrosome initiates maturation, reforming a second active MTOC. In yeast, differential microtubule growth has been attributed to the kinesin Kip2, which is specifically recruited to the old SPB (Chen et al, 2019). Kip2 prevents microtubule catastrophe and promotes microtubule extension (Carvalho et al, 2004;Cottingham and Hoyt, 1997;Hibbel et al, 2015;Huyett et al, 1998).…”

Section: Asymmetry Of the Cytoskeleton Centrosome Asymmetry And Biasementioning

confidence: 99%

Principles and mechanisms of asymmetric cell division

Sunchu

Cabernard

2020

Development

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Asymmetric cell division (ACD) is an evolutionarily conserved mechanism used by prokaryotes and eukaryotes alike to control cell fate and generate cell diversity. A detailed mechanistic understanding of ACD is therefore necessary to understand cell fate decisions in health and disease. ACD can be manifested in the biased segregation of macromolecules, the differential partitioning of cell organelles, or differences in sibling cell size or shape. These events are usually preceded by and influenced by symmetry breaking events and cell polarization. In this Review, we focus predominantly on cell intrinsic mechanisms and their contribution to cell polarization, ACD and binary cell fate decisions. We discuss examples of polarized systems and detail how polarization is established and, whenever possible, how it contributes to ACD. Established and emerging model organisms will be considered alike, illuminating both welldocumented and underexplored forms of polarization and ACD.

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Section: Asymmetry Of the Cytoskeleton Centrosome Asymmetry And Biasementioning

confidence: 99%

Principles and mechanisms of asymmetric cell division

Sunchu

Cabernard

2020

Development

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“…Spindle movements in budding yeast occur coincidentally with nuclear movement (due to the closed mitosis that takes place in this organism) and involves (1) alignment of the spindle along the mother-bud axis (a Kar9/actomyosin-mediated process), and (2) nuclear migration toward, and into the bud (a dynein-mediated process). Motor proteins are key effectors of this process since they can directly modulate microtubule dynamics (e.g., Kip2, Kip3), and generate pushing and pulling forces via astral microtubules (Carvalho et al, 2004;Chen et al, 2019;Fukuda et al, 13 2014). In tub1 G437R cells, orientation of the mitotic spindle along the mother-bud axis (by the Kar9/actomyosin pathway) was not apparently disrupted (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Modeling disease-correlated TUBA1A mutation in budding yeast reveals a molecular basis for tubulin dysfunction

Denarier

Ecklund

Berthier

et al. 2020

Preprint

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Malformations of cortical development (MCD) of the human brain are a likely consequence of defective neuronal migration, and/or proliferation of neuronal progenitor cells, both of which are dictated in part by microtubule-dependent transport of various cargoes, including the mitotic spindle. Throughout the evolutionary spectrum, proper spindle positioning depends on cortically anchored dynein motors that exert forces on astral microtubules emanating from spindle poles. A single heterozygous amino acid change, G436R, in the conserved TUBA1A α-tubulin gene was reported to account for MCD in patients. The mechanism by which this mutation disrupts microtubule function in the developing cerebral cortex is not understood.Studying the consequence of tubulin mutations in mammalian cells is challenging partly because of the large number of α-tubulin isotypes expressed. To overcome this challenge, we have generated a budding yeast strain expressing the mutated tubulin (Tub1 G437R in yeast) as one of the main sources of α-tubulin (in addition to Tub3, another α-tubulin isotype in this organism). Although viability of the yeast was unimpaired by this mutation, they became reliant on Tub3, as was apparent by the synthetic lethality of this mutant in combination with tub3∆. We find that Tub1 G437R assembles into microtubules that support normal G1 activity, but lead to enhanced dynein-dependent nuclear migration phenotypes during G2/M, and a consequential disruption of spindle positioning. We find that this mutation impairs the interaction between She1 -a negative regulator of dynein -and microtubules, as was apparent from a yeast two-hybrid assay, a co-sedimentation assay, and from live cell imaging.We conclude that a weaker interaction between She1 and Tub1 G437R -containing microtubules results in enhanced dynein activity, ultimately leading to the spindle positioning defect. Our results provide the first evidence of an impaired interaction between microtubules and a dynein regulator as a consequence of a tubulin mutation, and sheds light on a mechanism that may be causative of neurodevelopmental diseases.

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“…At the so-called minus end of microtubules, which is connected to the nucleation center, there is an α-tubulin subunit, while the β-tubulin subunit is located at the opposite side of the fiber, the so-called plus end. The minus end of the microtubule fiber is stabilized by a cap formed by a γ-tubulin subunit [ 5 ]. The basic and key property of these polymers is the so-called dynamic instability of microtubules [ 6 ].…”

Section: Microtubule Inhibitorsmentioning

confidence: 99%

“…Interestingly, much faster changes occur at the plus end of the fiber, i.e., on the opposite side to the nucleation center [ 7 ]. Microtubules are essential for maintaining the cell shape, polarity, migration and division [ 5 ]. Furthermore, they are utilized by protein motors kinesins and dyneins to transport molecules inside a cell [ 8 ].…”

Section: Microtubule Inhibitorsmentioning

confidence: 99%

Mitotic Poisons in Research and Medicine

et al. 2020

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Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are not available in more then 70% of low-income countries (90% of high-income countries have them available), and also approximately 70% of cancer deaths are reported in low-income countries. Various approaches on how to combat cancer diseases have since been described, targeting cell division being among them. The so-called mitotic poisons are one of the cornerstones in cancer therapies. The idea that cancer cells usually divide almost uncontrolled and far more rapidly than normal cells have led us to think about such compounds that would take advantage of this difference and target the division of such cells. Many groups of such compounds with different modes of action have been reported so far. In this review article, the main approaches on how to target cancer cell mitosis are described, involving microtubule inhibition, targeting aurora and polo-like kinases and kinesins inhibition. The main representatives of all groups of compounds are discussed and attention has also been paid to the presence and future of the clinical use of these compounds as well as their novel derivatives, reviewing the finished and ongoing clinical trials.

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Remote control of microtubule plus-end dynamics and function from the minus-end

Cited by 27 publications

References 66 publications

Principles and mechanisms of asymmetric cell division

Principles and mechanisms of asymmetric cell division

Modeling disease-correlated TUBA1A mutation in budding yeast reveals a molecular basis for tubulin dysfunction

Mitotic Poisons in Research and Medicine

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