Aurora A kinase regulates proper spindle positioning in C-elegans and in human cells

Accurate spindle positioning is essential for error-free cell division. The one-cell Caenorhabditis elegans embryo has proven instrumental for dissecting mechanisms governing spindle positioning. Despite important progress, how the cortical forces that act on astral microtubules to properly position the spindle are modulated is incompletely understood. Here, we report that the PP6 phosphatase PPH-6 and its associated subunit SAPS-1, which positively regulate pulling forces acting on spindle poles, associate with the Aurora A kinase AIR-1 in C. elegans embryos. We show that acute inactivation of AIR-1 during mitosis results in excess pulling forces on astral microtubules. Furthermore, we uncover that AIR-1 acts downstream of PPH-6-SAPS-1 in modulating spindle positioning, and that PPH-6-SAPS-1 negatively regulates AIR-1 localization at the cell cortex. Moreover, we show that Aurora A and the PP6 phosphatase subunit PPP6C are also necessary for spindle positioning in human cells. There, Aurora A is needed for the cortical localization of NuMA and dynein during mitosis. Overall, our work demonstrates that Aurora A kinases and PP6 phosphatases have an ancient function in modulating spindle positioning, thus contributing to faithful cell division.

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Coralie Busso, Pierre Gönczy, Sachin Kotak
2016
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https://infoscience.epfl.ch/record/222283?ln=fr

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Caenorhabditis elegans

Caenorhabditis elegans (C. elegans en abrégé) est un petit ver d'un millimètre environ, transparent et non parasitaire. C'est un nématode de la famille des Rhabditidae. Le nom est formé de

Mitose

droite|vignette|350px|La mitose est la formation de deux cellules filles identiques génétiquement à la cellule mère. La mitose, du grec mitos qui signifie « filament » (référence à l'aspect des chro

Cortex cellulaire

vignette|Distribution de la F-actine dans le cortex cellulaire, comme le montre la coloration à la rhodamine-phalloïdine de cellules HeLa qui expriment de façon constitutive l'Histone H2B-GFP pour mar

NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Galpha

Pierre Gönczy

The spindle apparatus dictates the plane of cell cleavage, which is critical in the choice between symmetric or asymmetric division. Spindle positioning is controlled by an evolutionarily conserved pathway, which involves LIN-5/GPR-1/2/Galpha in Caenorhabditis elegans, Mud/Pins/Galpha in Drosophila and NuMA/LGN/Galpha in humans. GPR-1/2 and Galpha localize LIN-5 to the cell cortex, which engages dynein and controls the cleavage plane during early mitotic divisions in C. elegans. Here we identify ASPM-1 (abnormal spindle-like, microcephaly-associated) as a novel LIN-5 binding partner. ASPM-1, together with calmodulin (CMD-1), promotes meiotic spindle organization and the accumulation of LIN-5 at meiotic and mitotic spindle poles. Spindle rotation during maternal meiosis is independent of GPR-1/2 and Galpha, yet requires LIN-5, ASPM-1, CMD-1 and dynein. Our data support the existence of two distinct LIN-5 complexes that determine localized dynein function: LIN-5/GPR-1/2/Galpha at the cortex, and LIN-5/ASPM-1/CMD-1 at spindle poles. These functional interactions may be conserved in mammals, with implications for primary microcephaly

2009

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lis-1 is required for dynein-dependent cell division processes in C. elegans embryos

Pierre Gönczy

We investigated the role of the evolutionarily conserved protein Lis1 in cell division processes of Caenorhabditis elegans embryos. We identified apparent null alleles of lis-1, which result in defects identical to those observed after inactivation of the dynein heavy chain dhc-1, including defects in centrosome separation and spindle assembly. We raised antibodies against LIS-1 and generated transgenic animals expressing functional GFP-LIS-1. Using indirect immunofluorescence and spinning-disk confocal microscopy, we found that LIS-1 is present throughout the cytoplasm and is enriched in discrete subcellular locations, including the cell cortex, the vicinity of microtubule asters, the nuclear periphery and kinetochores. We established that lis-1 contributes to, but is not essential for, DHC-1 enrichment at specific subcellular locations. Conversely, we found that dhc-1, as well as the dynactin components dnc-1 (p150Glued) and dnc-2 (p50/dynamitin), are essential for LIS-1 targeting to the nuclear periphery, but not to the cell cortex nor to kinetochores. These results suggest that dynein and Lis1, albeit functioning in identical processes, are targeted partially independently of one another.

2004

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Coupling of cortical dynein and Galpha proteins mediates spindle positioning in Caenorhabditis elegans

Pierre Gönczy

Despite being essential for spatial cell division control, the mechanisms governing spindle positioning remain incompletely understood. In the Caenorhabditis elegans one-cell stage embryo, the spindle becomes asymmetrically positioned during anaphase through the action of as-yet unidentified cortical force generators that pull on astral microtubules and that depend on two Galpha proteins and associated proteins. We performed spindle-severing experiments following temporally restricted gene inactivation and drug exposure, and established that microtubule dynamics and dynein are both required for generating efficient pulling forces. We found that the Galpha-associated proteins GPR-1/2 and LIN-5 interact in vivo with LIS-1, a component of the dynein complex. Moreover, we discovered that the LIN-5, GPR-1/2 and the Galpha proteins promote the presence of the dynein complex at the cell cortex. Our findings suggest a mechanism by which the Galpha proteins enable GPR-1/2 and LIN-5 recruitment to the cortex, thus ensuring the presence of cortical dynein. Together with microtubule dynamics, this allows pulling forces to be exerted and proper cell division to be achieved.

2007

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