Emi2 enables centriole amplification during multiciliated cell differentiation

Kim, Seongjae; Chien, Yuan-Hung; Ryan, Amy L.; Kintner, Chris

doi:10.1126/sciadv.abm7538

Cited by 12 publications

(12 citation statements)

References 47 publications

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“…This would eventually lead to an entire decoupling between the nuclear and cytoplasmic compartments, as seen in developing fly blastoderms (31). Since decoupling between centrosome and nuclear cycles can also be obtained by dampening CDK activity in cycling cells (32,33) and that DNA replication and mitotic events can be restored in cells undergoing this MCC cell cycle variant by disinhibiting CDK activity (3,5), we suggest the existence of a cytoplasmic -or centriolar-CDK threshold, lower than the S-phase threshold. A quantitative control of CDK activity by APC/C and the regulated expression of its inhibitors Emi1/2 would thus allow the progression of a purely cytoplasmic MCC cell cycle variant.…”

Section: Discussionmentioning

confidence: 86%

“…Pharmaceutical modulation of the activity of these cell cycle factors induces major defects in numbers of generated centrioles and in the dynamics of their formation, as well as in motile ciliation in terminally differentiated MCCs. They can also induce mitosis-like features and abnormal DNA replication ( 3 , 5 ). Here we use single-cell RNA-seq experiments to investigate the co-option of cell cycle factors, coupled with functional assays to study the role of cyclins during MCC differentiation.…”

Section: Main Textmentioning

confidence: 99%

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Identification of a new cell cycle variant during multiciliated cell differentiation

Serizay,

Damaa,

Boudjema

et al. 2024

Preprint

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A complex and conserved regulatory network drives the cell cycle. Individual components of this network are sometimes used in differentiated cells, i.e. to control organelle destruction in mammalian lens cells or light response in land plants. Some differentiated cells co-opt cell-cycle regulators more largely, to increase their ploidy using a cell cycle variant named endoreplication. Using single-cell RNA-seq profiling and functional assays in differentiating multiciliated cells, we identified a novel type of cell cycle variant that supports cytoplasmic organelle, rather than nuclear content amplification. This variant operates in post-mitotic, centriole-amplifying differentiating multiciliated cells and is characterized by (i) a circular trajectory of the transcriptome, (ii) sequential expression of more than 70% of the genes involved in S, G2 and M-like progression along this trajectory, and (iii) successive waves of cyclins. This cell cycle variant is tailored by the expression of the non-canonical cyclins O and A1 - which replace the transcriptionally silent cyclins E2 and A2 - and by the silencing of the APC/C inhibitor Emi1, two switches also detected in male meiosis, another variant of the canonical cell cycle where centriole and DNA replications are uncoupled. Re-expressing Cyclin E2, cyclin A2 or Emi1 is sufficient to induce partial replication and mitosis, suggesting that change in the regulation of expression of a few cell cycle key players drives a qualitative and quantitative tuning of Cdk activity, allowing the diversion of the cell cycle in the multiciliation variant. We also propose that this new cell cycle variant relies on the existence of a cytoplasmic - or centriolar - Cdk threshold, lower than the S-phase threshold, which affects only the cytoplasmic reorganization.

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Section: Discussionmentioning

confidence: 86%

Section: Main Textmentioning

confidence: 99%

Identification of a new cell cycle variant during multiciliated cell differentiation

Serizay,

Damaa,

Boudjema

et al. 2024

Preprint

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“…Most surprisingly, centriole disengagement, which is known to be Plk1 and APC/C dependent (Al Jord et al, 2017; Kim et al, 2022; Ruiz García et al, 2019), is tightly correlated with this nuclear association. First, the migration of procentriole loaded deuterosomes systematically precedes centriole disengagement.…”

Section: Discussionmentioning

confidence: 99%

“…Since live observations are difficult in respiratory MCCs, the stages of amplification have been finely described by immunostainings (Zhao et al, 2013, 2021). Molecular examination by immunostainings and loss of function experiments on both mouse brain and respiratory MCCs showed that the cell cycle regulators and the centriole duplication molecular cascade used by cycling cells are co-opted in differentiating MCCs to control centriole number, growth and disengagement (Al Jord et al, 2017; Kim et al, 2022; LoMastro et al, 2022; Revinski et al, 2018; Vladar et al, 2018; Vladar & Stearns, 2007).…”

Section: Introductionmentioning

confidence: 99%

Microtubule-dependent orchestration of centriole amplification in brain multiciliated cells

Boudjema,

Balagué,

Jewett

et al. 2024

Preprint

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Centriole number must be restricted to two in cycling cells to avoid pathological cell divisions. Multiciliated cells (MCC), however, need to produce a hundred or more centrioles to nucleate the same number of motile cilia required for fluid flow circulation. These centrioles are produced by highjacking cell cycle and centriole duplication programs. However, how the MCC progenitor handles such a massive number of centrioles to finally organize them in an apical basal body patch is unclear. Here, using new cellular models and high-resolution imaging techniques, we identify the microtubule network as the bandleader, and show how it orchestrates the process in space and in time. Organized by the pre-existing centrosome at the start of amplification, microtubules build a nest of centriolar components from which procentrioles emerge. When amplification is over, the centrosome's dominance is lost as new centrioles mature and become microtubule nucleators. Microtubules then drag all the centrioles to the nuclear membrane, assist their isotropic perinuclear disengagement and their subsequent collective apical migration. These results reveal that in brain MCC as in cycling cells, the same dynamics -from the centrosome to the cell pole via the nucleus- exists, is the result of a reflexive link between microtubules and the progressive maturation of new centrioles, and participates in the organized reshaping of the entire cytoplasm. On the other hand, new elements described in this work such as microtubule-driven organization of a nest, identification of a spatio-temporal progression of centriole growth and microtubule-assisted disengagement, may shed new light on the centriole duplication program.

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“…In the case of GEMININ, and likely MCIDAS, this requires APC/C CDC20 [2,61]. Moreover, recent work demonstrated that Emi2, a negative regulator of APC/CDH1, is upregulated by MCIDAS and plays an important role in multiciliation [62]. The emerging picture suggests that GEMC1 and MCIDAS both activate and are targets of cell cycle-specific regulatory proteins, providing an elegant mechanism to facilitate their stepwise actions and fine tune transcriptional output with massive centriole amplification.…”

Section: Discussionmentioning

confidence: 99%

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program

et al. 2023

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Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.

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Emi2 enables centriole amplification during multiciliated cell differentiation

Cited by 12 publications

References 47 publications

Identification of a new cell cycle variant during multiciliated cell differentiation

Identification of a new cell cycle variant during multiciliated cell differentiation

Microtubule-dependent orchestration of centriole amplification in brain multiciliated cells

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program

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