Cyclin-dependent kinase control of motile ciliogenesis

Vladar, Eszter K.; Stratton, Miranda B.; Saal, Maxwell L.; Simone, Glicella Salazar-De; Wang, Xiangyuan; Wolgemuth, Debra J.; Stearns, Tim; Axelrod, Jeffrey

doi:10.7554/elife.36375

Cited by 47 publications

(35 citation statements)

References 50 publications

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“…In the case of RIBC2 , which is known to function within the cell cycle (Giotti et al, 2018), the gene also influences motile ciliary beating in Chlamydomonas , where it has shown to colocalized to the axoneme (Chung et al, 2014). Such findings of multifunctional genes add to the emerging literature on the alternative regulation of centrosomal and cell cycle genes for motile- and multi-ciliogenesis or associated with their function, as also suggested by their coexpression with FOXJ1 across tissue from the GTEx (Vladar et al, 2018, Zhao et al, 2013, Balestra and Gönczy, 2014). Indeed, studies have found certain cell cycle genes uniquely regulated through alternative promoter usage depending on the cell type (Giotti et al, 2018).…”

Section: Discussionsupporting

confidence: 56%

The transcriptional signature associated with human motile cilia

Patir

Fraser

Barnett

et al. 2019

Preprint

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Cilia are complex microtubule-based organelles implicated in the aetiology of numerous diseases. Accordingly, many cilia-associated proteins have been described, while those distinguishing cilia subtypes are poorly defined. Here, we characterise the gene signature associated with human motile cilia that captures both known and unknown components of this class of cilia. To define the signature, we performed network deconvolution of transcriptomics data derived from tissues possessing motile ciliated cell populations. For each tissue, genes coexpressed with the motile cilia-associated transcriptional factor, FOXJ1, were identified. The consensus across tissues provided a transcriptional signature of 248 genes. For validation, we examined the literature, databases, single cell RNA-Seq data, and the localisation of mRNA and proteins in motile ciliated cells. To validate some of the many poorly characterised genes, we performed new localisation experiments on ARMC3, EFCAB6, FAM183A, MYCBPAP, RIBC2 and VWA3A. In summary, we report a highly validated set of motile cilia-associated genes that helps shape our understanding of these complex cellular organelles.SummaryThis work defines a conserved transcriptional signature associated with human motile cilia, including many genes with little or no previous association with these structures. These genes were compared with existing resources and a number of poorly characterised genes validated.Graphical abstract

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Section: Discussionsupporting

confidence: 56%

The transcriptional signature associated with human motile cilia

Patir

Fraser

Barnett

et al. 2019

Preprint

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“…Another study found that CDK2, the kinase responsible for G1-S phase transition, was also required in MCC to initiate the motile ciliogenesis program independent of cell cycle progression 47 . Thus, 11 one possible reason for the elevated Plk4 protein is to coordinate the timing of centriole assembly and maturation in post-mitotic cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cilia Abundance in Multiciliated Cells

Nanjundappa¹,

Kong

Shim³

et al. 2018

Preprint

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Multiciliated cells (MCC) are specialized epithelia that contain hundreds of motile cilia used to propel fluid over the surface of the cell. To template these cilia, each MCC produces hundreds of centrioles by a process termed centriole amplification. Airway progenitor cells initially contain two parental centrioles that nucleate multiple centrioles at once, and structures called deuterosomes that assemble the vast majority of centrioles during amplification. Remarkably, how each cell regulates the precise number of its centrioles and cilia remains unknown. Here, we investigate mechanisms that establish centriole number in MCC using an ex vivo airway culture model. We show that ablation of parental centrioles, via inhibition of Plk4 kinase, does not perturb deuterosome formation and centriole amplification, nor alter the total complement of centrioles per cell. Airway MCC vary in size and surface area, and exhibit a broad range in centriole number. Quantification of centriole abundance in vitro and in vivo identified a direct relationship between cell-surface area and centriole number. By manipulating cell size and shape, we discovered that centriole number scales with increasing surface area. Collectively, our results demonstrate that parental centrioles and Plk4 are dispensable for deuterosome formation, centriole amplification, and establishment of centriole number. Instead, a cell-intrinsic surface area-dependent mechanism controls centriole and cilia abundance in multiciliated cells.

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“…This amplification occurs through the formation of intermediate organelles, the deuterosomes, which are composed of centrosome-related elements 2,3 . Deuterosomes support massive centriole production within a molecular cascade that is shared with the cell cycle centrosome duplication program [3][4][5] . Because two centrosomal centrioles seemed insufficient to scaffold the formation of tens of centrioles, massive centriole production through deuterosome structures was proposed to arise independently from the centrosome in MCC 6 .…”

Section: Introductionmentioning

confidence: 99%

Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors

Mercey

Jord

Rostaing

et al. 2018

Preprint

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Centrioles are essential microtubule-based organelles organizing cilia and centrosomes. Their mode of biogenesis is semi-conservative: each pre-existing centriole scaffolds the formation of a new one, a process coordinated with the cell cycle. By contrast, multiciliated progenitors with two centrosomal centrioles massively amplify centrioles to support the nucleation of hundred of motile cilia and transport vital fluids. This occurs through cell type-specific organelles called deuterosomes, composed of centrosome-related elements, and is regulated by the cell cycle machinery. Deuterosome-dependent centriole amplification was proposed for decades to occur de novo, i.e. independently from preexisting centrioles. Challenging this hypothesis, we recently reported an accumulation of procentriole and deuterosome precursors at the centrosomal daughter centriole during centriole amplification in brain multiciliated cells. Here we further investigate the relationship between the centrosome and the dynamic of centriole amplification by (i) characterizing the centrosome behavior during the centriole amplification dynamics and (ii) assessing the dynamics of amplification in centrosome-depleted cells. Surprisingly, although our data strengthen the centrosomal origin of amplified centrioles, we show limited consequences in deuterosome/centriole number when we deplete centrosomal centrioles.

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Cyclin-dependent kinase control of motile ciliogenesis

Cited by 47 publications

References 50 publications

The transcriptional signature associated with human motile cilia

The transcriptional signature associated with human motile cilia

Regulation of Cilia Abundance in Multiciliated Cells

Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors

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