Cortical dynein is critical for proper spindle positioning in human cells

Kotak, Sachin; Busso, Coralie; Gönczy, Pierre

doi:10.1083/jcb.201203166

Cited by 221 publications

(304 citation statements)

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“…3A) (Wang et al, 2011). Recent evidence also suggests that a cortically localized component of dynein, via specific interaction with Mud, is required for proper spindle orientation (Kotak et al, 2012). Thus, Mud facilitates a link between the dynein motor complex and cortically polarized Pins.…”

Section: Reviewmentioning

confidence: 99%

Molecular pathways regulating mitotic spindle orientation in animal cells

2013

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Orientation of the cell division axis is essential for the correct development and maintenance of tissue morphology, both for symmetric cell divisions and for the asymmetric distribution of fate determinants during, for example, stem cell divisions. Oriented cell division depends on the positioning of the mitotic spindle relative to an axis of polarity. Recent studies have illuminated an expanding list of spindle orientation regulators, and a molecular model for how cells couple cortical polarity with spindle positioning has begun to emerge. Here, we review both the wellestablished spindle orientation pathways and recently identified regulators, focusing on how communication between the cell cortex and the spindle is achieved, to provide a contemporary view of how positioning of the mitotic spindle occurs.Key words: Spindle, Microtubules, Oriented cell division, Polarity, Mitosis, Centrosome IntroductionAll multicellular animals are tasked with two fundamental developmental challenges: generating cellular diversity and forming three-dimensional tissues, both of which initiate from a singlecelled zygote. Cellular diversity is spawned by cell divisions yielding non-identical daughters, and tissue morphogenesis is established through the precise three-dimensional arrangement of cell divisions that form the overall architecture of the organism. Both of these essential challenges are resolved in part through oriented cell division, which regulates embryogenesis, organogenesis and cellular differentiation. Notably, oriented cell divisions, and hence asymmetric cell divisions, remain crucial throughout adulthood as well, functioning as the basis for tissue homeostasis during growth and wound repair. One primary feature of oriented cell division is the proper positioning of the mitotic spindle relative to a defined polarity axis. In principle, spindle orientation is achieved through signaling pathways that provide a molecular link between the cell cortex and spindle microtubules. These pathways are thought to elicit both static connections and dynamic forces on the spindle to achieve the desired orientation prior to cell division. Although our knowledge of the signaling molecules involved in this process and our understanding of how they each function at the molecular level remain limited, collective efforts over the years have shed light on the importance of spindle orientation to animal development and function. Moreover, emerging evidence shows an association between improper spindle orientation and a number of developmental diseases as well as tumor formation. The study of spindle orientation is therefore fundamental to both developmental biology and human disease.Over a century ago, Oscar Hertwig discovered that sea urchin embryos biased the orientation of the mitotic spindle along their long axis, which led to a model (the 'Hertwig Rule') in which cells orient divisions in response to mechanical forces (Hertwig, 1884). The Hertwig model stated that mechanical regulation was the primary determinant of spindle orien...

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Section: Reviewmentioning

confidence: 99%

Molecular pathways regulating mitotic spindle orientation in animal cells

2013

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“…However, the preference of NuMA 'C' for spindle ends was clear. Because dynein-dynactin interacts with NuMA's N-terminus (Kotak et al, 2012), the minus-end localization of NuMA's C-terminus provides further support for dynein-independent minus-end recognition.…”

Section: Numa Localizes To Minus-ends Independently Of Known Minus-enmentioning

confidence: 99%

“…This suggests that NuMA's function in spindle organization requires both minus-end binding (via its C-terminus) and the ability to recruit dynactin to minus-ends (via its N-terminus) (Kotak et al, 2012). Consistent with this hypothesis, NuMA's C-terminus ('C') was unable to recruit dynactin to minus-ends, while its N-terminus and C-terminus fused ('N-C') did ( Figure 6E; Table 1).…”

Section: Numa Localizes To Minus-ends Independently Of Known Minus-enmentioning

confidence: 99%

“…NuMA's pole-focusing ability correlates with dynactin-and minus-end-binding. See also Figure 6 and Localizes to preferentially to minus-ends (Kotak et al, 2012). 'C-tail2' was previously implicated in microtubule (MT) binding (Chang et al, 2017;Du et al, 2002;Gallini et al, 2016; Figure 6 continued on next page domain ('N-Tau').…”

Section: Numa Localizes To Minus-ends Independently Of Known Minus-enmentioning

confidence: 99%

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NuMA Recruits Dynein Activity to Microtubule Minus-Ends at Mitosis

Hueschen

Kenny

et al. 2018

Biophysical Journal

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To build the spindle at mitosis, motors exert spatially regulated forces on microtubules. We know that dynein pulls on mammalian spindle microtubule minus-ends, and this localized activity at ends is predicted to allow dynein to cluster microtubules into poles. How dynein becomes enriched at minus-ends is not known. Here, we use quantitative imaging and laser ablation to show that NuMA targets dynactin to minus-ends, localizing dynein activity there. NuMA is recruited to new minus-ends independently of dynein and more quickly than dynactin; both NuMA and dynactin display specific, steady-state binding at minus-ends. NuMA localization to minus-ends involves a C-terminal region outside NuMA's canonical microtubule-binding domain and is independent of minus-end binders g-TuRC, CAMSAP1, and KANSL1/3. Both NuMA's minus-endbinding and dynein-dynactin-binding modules are required to rescue focused, bipolar spindle organization. Thus, NuMA may serve as a mitosis-specific minus-end cargo adaptor, targeting dynein activity to minus-ends to cluster spindle microtubules into poles.

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“…Dynein anchored by Gα-GPR-LIN-5 attaches microtubule plus ends to the cell cortex, while depolymerization of the microtubules ends is thought to be largely responsible for force generation (Kozlowski et al 2007;Nguyen-Ngoc et al 2007;Laan et al 2012). Myristoylation of the Gα subunit allows membrane attachment of the complex, and, based on the analysis of human NuMA, the N-terminal part of LIN-5/NuMA mediates dynein interaction (Kotak et al 2012). While these molecular interactions are conserved in the animal kingdom, variations are used in development.…”

Section: The Trimeric Gα-gpr-lin-5 Complex Recruits Dynein To the Cortexmentioning

confidence: 99%

Polarity Control of Spindle Positioning in the C. elegans Embryo

Fielmich

Heuvel

2015

Cell Polarity 2

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Cell and tissue polarity guides a large variety of developmental processes, including the choice between symmetric and asymmetric cell division. Asymmetric divisions create cell diversity and are needed for the maintenance of tissue-specific stem cells. Symmetric divisions, on the other hand, promote exponential cell proliferation. Polarized cells often divide symmetrically by cleaving along the axis of polarity. Alternatively, cell cleavage in a plane perpendicular to the polarity axis results in asymmetric division. To control this decision, developmental cues position the mitotic spindle, which instructs the plane of cell cleavage. In animal cells, the positioning of the spindle depends on evolutionarily conserved interactions between a heterotrimeric G-protein alpha subunit, TPR-GoLoco domain protein, and NuMA-related coiled-coil protein. This trimeric complex recruits the dynein microtubule motor and captures astral microtubules at the cortex. The interplay between dynein movement and depolymerizing microtubules generates cortical pulling forces that promote aster movement and spindle positioning. Through mechanisms that are poorly understood, cell polarity and other developmental signals control the microtubule-pulling forces to instruct the orientation and plane of cell division. In this chapter, we review the current understanding of the connection between cell polarity and spindle positioning, with a focus on studies of the early C. elegans embryo. The nematode C. elegans develops through a highly reproducible division pattern and has proven to be a powerful model for studying the regulation and execution of asymmetric cell division.

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Cortical dynein is critical for proper spindle positioning in human cells

Abstract: Dynein is anchored at the plasma membrane by a ternary complex comprising NuMA–LGN–Gα and thus ensures correct spindle positioning

Cited by 221 publications

References 55 publications

Molecular pathways regulating mitotic spindle orientation in animal cells

Molecular pathways regulating mitotic spindle orientation in animal cells

NuMA Recruits Dynein Activity to Microtubule Minus-Ends at Mitosis

Polarity Control of Spindle Positioning in the C. elegans Embryo

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