PLK4 drives centriole amplification and apical surface area expansion in multiciliated cells

LoMastro, Gina M.; Drown, Chelsea G; Maryniak, Aubrey L; Jewett, Cayla E.; Strong, Margaret A.; Holland, Andrew J.

doi:10.7554/elife.80643

Cited by 15 publications

(12 citation statements)

References 54 publications

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“…Centriole biogenesis during multiciliate cell differentiation is accomplished through the same regulators that are required for centriole duplication during the cell cycle and Al Jord et al proved that proteins that control cell cycle progression are also essential to drive multiciliated cell differentiation (Al Jord et al, 2017). Very recently, it was suggested that PLK4 protein and its kinase activity are essential for centriole amplification in multiciliated cells (LoMastro et al, 2022). These results corroborate the idea that the initial stages of centriole assembly are conserved between cycling…”

Section: Previous Work Showed That Mcidas Forms a Stable Complex With...mentioning

confidence: 62%

McIdas localizes at centrioles and controls centriole numbers through PLK4-dependent phosphorylation

Arbi

Skamnelou

Bournaka

et al. 2022

Preprint

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The centriole duplication cycle must be tightly controlled and coordinated with the chromosome cycle. Aberrations in centriole biogenesis can lead to cancer, developmental disorders and ciliopathies. Here, we show that McIdas -previously implicated in cell cycle control and centriole amplification in multiciliated cells- is critical to maintain centriole numbers. Using expansion microscopy, we demonstrate that McIdas is present at the middle part of centrioles, where it exhibits a differential localization during the cell cycle. McIdas loss perturbs daughter centriole biogenesis and centrosomal SAS6 recruitment, whereas its overexpression induces centriole overduplication. Consistently, McIdas depletion reduces PLK4-induced centriole amplification. McIdas interacts with and is phosphorylated by PLK4 in multiple sites identified by mass spectrometry. Mutational analysis shows that McIdas phosphorylation is important for centriole number control. Overall, our results identify a novel, direct role of McIdas on centriole duplication that can link its previously characterized roles in the chromosome cycle and multiciliogenesis.

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Section: Previous Work Showed That Mcidas Forms a Stable Complex With...mentioning

confidence: 62%

McIdas localizes at centrioles and controls centriole numbers through PLK4-dependent phosphorylation

Arbi

Skamnelou

Bournaka

et al. 2022

Preprint

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“…Recent studies have revealed that PLK4 induced centrosome amplification is not only present in cancer cells but is also necessary for generating multiciliated cells [17, 44]. Previous research demonstrated that inducing PLK4 expression in human cells leads to centrosome rosettes (CRs) in the first cell cycle [19], followed by centrosome amplification in the second cell cycle [8].…”

Section: Discussionmentioning

confidence: 99%

Prolonged over-expression of PLK4 amplifies centrosomes through formation of inter-connected centrosome rosette clusters

Özcan,

Kalkan,

Çiçek

et al. 2023

Preprint

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he centrosome cycle is a tightly regulated process to ensure proper segregation of chromosomes. Not surprisingly, centriole number is tightly controlled via multiple mechanisms, one of which involves PLK4, an upstream kinase facilitating centriole biogenesis and duplication. Aberrations in this process can result in supernumerary centrosomes, which are frequently observed in a variety of cancers due to high levels of PLK4. Interestingly, extra centrosomes induced by PLK4 over-expression go through unique intermediate structures called the centrosome rosettes (CRs), where the mother centriole is surrounded by numerous daughter centrioles. The maturation and molecular nature of these CRs have not been investigated in detail. Upon prolonged PLK4 over-expression, cells exhibited large centrosomes that were clustered and contained more than two CRs, which we defined as centrosome rosette clusters (CRCs). As expected, these structures required high PLK4 levels at two consecutive cell cycles and were still interconnected with canonical centrosomal linker proteins such as C-Nap1, Rootletin, and Cep68. Knockout of these linker proteins resulted in distancing of CRs and CRCs as observed by increased diameter of the CRCs in interphase. In contrast, Nek2 knockout inhibited the separation of CRCs in prometaphase, providing functional evidence for the binding of CRC structures with centrosomal linker proteins. These results suggest a cell cycle dependent model for PLK4 induced centrosome amplification, which occurs in two consecutive cell cycles: (i) CR state in the first cell cycle, and (ii) CRC state in the second cell cycle.

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“…Coverslips were mounted in ProLong TM Gold Antifade (ThermoFisher Scientific) or home-made mounting solution (23 % polyvinyl alcohol, 63 % glycerol and 0,02 % NaN3 in PBS). The following antibodies were used to perform immunofluorescence staining in murine cells: rabbit polyclonal α-CEP152 1:1000 (homemade, LoMastro et al ., 2022, 1:1000), goat polyclonal α-ɣ-Tubulin (homemade, Levine et al ., 2017, 1:1000), rabbit polyclonal α-CEP135 (homemade, LoMastro et al ., 2022, 1:1000), mouse α-ɣ-Tubulin (Sigma-Aldrich, 1:250); rabbit α-CP110 (Protein Tech, 12780-1-AP, 1:500), goat α-mouse IgG AF568 (Thermo Fisher, A11031, 1:1000), goat α-rabbit IgG AF488 (Thermo Fisher, A-11034, 1:1000).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were again washed 3 x with washing buffer.When Höchst 3342 (Sigma-Aldrich 23491-52) was used it was added in the last washing step.Coverslips were mounted in ProLong TM Gold Antifade (ThermoFisher Scientific) or home-made mounting solution (23 % polyvinyl alcohol, 63 % glycerol and 0,02 % NaN3 in PBS). The following antibodies were used to perform immunofluorescence staining in murine cells: rabbit polyclonal α-CEP152 1:1000(homemade, LoMastro et al, 2022(homemade, LoMastro et al, , 1:1000, goat polyclonal α-ɣ-Tubulin (homemade,Levine et al, 2017Levine et al, , 1:1000, rabbit polyclonal α-CEP135 (homemade,LoMastro et al, 2022LoMastro et al, , 1:1000, mouse α-ɣ-Tubulin (Sigma-Aldrich, 1:250); rabbit α-CP110 (Protein Tech, 12780-1-AP, 1:500), goat α -mouse IgG AF568 (Thermo Fisher, A11031, 1:1000), goat α -rabbit IgG AF488 (Thermo Fisher, A-11034, 1:1000).Thirty to fifty Z-stacks were acquired at room temperature on Zeiss Axiovert 200M microscope with an oil immersion objective (Ph3 Plan-Neofluar 100×/1.3 oil, 440481, Zeiss) using the acquisition software VisiView 4.1.0.3. Maximum stack projections of z-stacks were performed using the VisiView 4.1.0.3.…”

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confidence: 99%

Exact centriole counts are critical for B cell development but not function

Schapfl,

LoMastro,

Braun

et al. 2024

Preprint

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Centrioles define centrosome structure and function. Deregulation of centriole numbers can cause developmental defects and foster malignant disease. The p53 tumor suppressor limits the growth of cells lacking or harboring additional centrioles and can be engaged by the 'mitotic surveillance' or the 'PIDDosome pathway', respectively. Here, we show that early B cell progenitors frequently present extra centrioles that are rapidly lost during maturation. Increasing centriole counts beyond physiological levels by Polo-like kinase 4 (PLK4) overexpression induces apoptosis, suggesting clearance of such cells during development. Remarkably, this apoptotic response is independent of PIDD1 or p53, but can be blocked by excess BCL2. In contrast, loss of centrosomes upon Plk4 deletion arrests B cell development at the pro B cell stage. This defect can be rescued by co-deletion of Usp28, a critical component of the mitotic surveillance pathway that restores cell number and function in the absence of centrioles. In both scenarios, too many and too few centrosomes, mitochondrial apoptosis is engaged to kill B cells with abnormal centriole counts during their development with progenitor B cells being intolerant to centriole loss but permissive to centriole amplification. Unexpectedly, our findings show that centrioles are dispensable for mounting an effective humoral immune response.

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PLK4 drives centriole amplification and apical surface area expansion in multiciliated cells

Cited by 15 publications

References 54 publications

McIdas localizes at centrioles and controls centriole numbers through PLK4-dependent phosphorylation

McIdas localizes at centrioles and controls centriole numbers through PLK4-dependent phosphorylation

Prolonged over-expression of PLK4 amplifies centrosomes through formation of inter-connected centrosome rosette clusters

Exact centriole counts are critical for B cell development but not function

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