A centrosome‐localized calcium signal is essential for mammalian cell mitosis

Helassa, Nordine; Nugues, Charlotte; Rajamanoharan, Dayani; Burgoyne, Robert D.; Haynes, Lee P.

doi:10.1096/fj.201901662r

Cited by 18 publications

(18 citation statements)

References 51 publications

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“…The defects are reversed by expression of IP 3 R3, but only if it has a functional Ca 2+ pore ( Figure 4 ). This is consistent with recent work suggesting that local Ca 2+ signals occur near centrosomes throughout mitosis, and abolishing them at one centrosome perturbs mitosis ( Helassa et al., 2019 ). It is noteworthy that variations in expression of endogenous IP 3 Rs are associated with the reliability of spindle alignment: WT cells with fewer IP 3 Rs are more likely to have misaligned spindles ( Figure S3 A).…”

Section: Discussionsupporting

confidence: 93%

“…We conclude that Ca 2+ release through IP 3 Rs is required for the mitotic spindle to align appropriately, probably through regulation of astral microtubules by IP 3 R-evoked Ca 2+ signals ( Figure 4 D). Future experiments should assess whether the Ca 2+ signals that occur during metaphase ( Helassa et al., 2019 ) regulate microtubules and their motors or deliver Ca 2+ locally to the mitochondria to allow local delivery of ATP ( Zhao et al., 2019 ) and thereby regulation of microtubule activity. Our results reveal that IP 3 R-evoked Ca 2+ signals are an important means of regulating the mitotic spindle.…”

Section: Discussionmentioning

confidence: 99%

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Ca2+ Release by IP3 Receptors Is Required to Orient the Mitotic Spindle

2020

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Summary The mitotic spindle distributes chromosomes evenly to daughter cells during mitosis. The orientation of the spindle, guided by internal and external cues, determines the axis of cell division and thereby contributes to tissue morphogenesis. Progression through mitosis requires local Ca 2+ signals at critical steps, and because store-operated Ca 2+ entry is inhibited during mitosis, those signals probably require Ca 2+ release through inositol 1,4,5-trisphosphate receptors (IP 3 Rs). In cells without IP 3 Rs, astral microtubules around the daughter centrosome are shorter than those at the mother centrosome, and the mitotic spindle fails to align with the substratum during metaphase. The misalignment is due to the spindle ineffectively detecting internal cues rather than a failure of cells to recognize the substratum. Expression of type 3 IP 3 R is sufficient to rescue spindle alignment, but only if the IP 3 R has a functional pore. We conclude that Ca 2+ signals evoked by IP 3 Rs are required to orient the mitotic spindle.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Ca2+ Release by IP3 Receptors Is Required to Orient the Mitotic Spindle

2020

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“…More recent studies demonstrated that chromosome condensation is influenced by Ca 2+ [64] . In addition, spatial restriction of a genetically encoded Ca 2+ sensor detected a focally restricted centrosome-based Ca 2+ signal in mitotic cells [65] . These findings are helping to clarify the crucial yet incompletely defined link between Ca 2+ signaling, cell cycle progression, arrest and apoptosis [66] .…”

Section: Discussionmentioning

confidence: 99%

“…Diffusion of Ca 2+ in the nucleus promotes transition of chromatin structure from fibrous to globular, chromosome condensation, mitosis and cell proliferation. [64] , [65] , [66] …”

Section: Discussionmentioning

confidence: 99%

A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice

et al. 2020

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Background Numerous currently incurable human diseases have been causally linked to mutations in connexin (Cx) genes. In several instances, pathological mutations generate abnormally active Cx hemichannels, referred to also as “leaky” hemichannels. The goal of this study was to assay the in vivo efficacy of a potent antagonist antibody targeting Cx hemichannels. Methods We employed the antibody to treat Cx30 A88V/A88V adult mutant mice, the only available animal model of Clouston syndrome, a rare orphan disease caused by Cx30 p.A88V leaky hemichannels. To gain mechanistic insight into antibody action, we also performed patch clamp recordings, Ca 2+ imaging and ATP release assay in vitro . Findings Two weeks of antibody treatment sufficed to repress cell hyperproliferation in skin and reduce hypertrophic sebaceous glands (SGs) to wild type (wt) levels. These effects were obtained whether mutant mice were treated topically, by application of an antibody cream formulation, or systemically, by intraperitoneal antibody injection. Experiments with mouse primary keratinocytes and HaCaT cells revealed the antibody blocked Ca 2+ influx and diminished ATP release through leaky Cx30 p.A88V hemichannels. Interpretation Our results show anti-Cx antibody treatment was effective in vivo and sufficient to counteract the effects of pathological connexin expression in Cx30 A88V/A88V mice. In vitro experiments suggest antibodies gained control over leaky hemichannels and contributed to restoring epidermal homeostasis. Therefore, regulating cell physiology by antibodies targeting the extracellular domain of Cxs may enforce an entirely new therapeutic strategy. These findings support the further development of antibodies as drugs to address unmet medical needs for Cx-related diseases. Fund Fondazione Telethon, GGP19148; University of Padova, SID/BIRD187130; Consiglio Nazionale delle Ricerche, DSB.AD008.370.003\TERABIO-IBCN; National Science Foundation of China, 31770776; Science and Technology Commission of Shanghai Municipality, 16DZ1910200.

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“…Lysosomal clustering at the intercellular bridge has been suggested to promote the activities at the cleavage furrow (Rajamanoharan et al, 2015). Recent data indicate that phosphoinositol-4-kinase-dependent lysosome exocytosis provides membranous material to the furrow, and inhibiting this process causes mitotic failures (Helassa et al, 2019). Before the final cut, the portioning of endolysosomal vesicles into daughter cells occurs in an ordered, yet imprecise, manner.…”

Section: The Separation and The Final Cut: Vesicles On The Movementioning

confidence: 99%

They Might Cut It—Lysosomes and Autophagy in Mitotic Progression

Hämälistö

Stahl-Meyer

Jäättelä

2021

Front. Cell Dev. Biol.

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The division of one cell into two looks so easy, as if it happens without any control at all. Mitosis, the hallmark of mammalian life is, however, tightly regulated from the early onset to the very last phase. Despite the tight control, errors in mitotic division occur frequently and they may result in various chromosomal instabilities and malignancies. The flow of events during mitotic progression where the chromosomes condensate and rearrange with the help of the cytoskeletal network has been described in great detail. Plasma membrane dynamics and endocytic vesicle movement upon deadhesion and reattachment of dividing cells are also demonstrated to be functionally important for the mitotic integrity. Other cytoplasmic organelles, such as autophagosomes and lysosomes, have until recently been considered merely as passive bystanders in this process. Accordingly, at the onset of nuclear envelope breakdown in prometaphase, the number of autophagic structures and lysosomes is reduced and the bulk autophagic machinery is suppressed for the duration of mitosis. This is believed to ensure that the exposed nuclear components are not unintentionally delivered to autophagic degradation. With the evolving technologies that allow the detection of subtle alterations in cytoplasmic organelles, our understanding of the small-scale regulation of intracellular organelles has deepened rapidly and we discuss here recent discoveries revealing unexpected roles for autophagy and lysosomes in the preservation of genomic integrity during mitosis.

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A centrosome‐localized calcium signal is essential for mammalian cell mitosis

Cited by 18 publications

References 51 publications

Ca2+ Release by IP3 Receptors Is Required to Orient the Mitotic Spindle

Ca2+ Release by IP3 Receptors Is Required to Orient the Mitotic Spindle

A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice

They Might Cut It—Lysosomes and Autophagy in Mitotic Progression

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