Genes regulated by MCIDAS
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ABSTRACT:
PROVIDER: PRJEB77353 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Multiciliated cells are crucial for fluid and ion transport in epithelia of a variety of organs and their impaired development and function are seen in human diseases affecting the brain, respiratory, and reproductive tracts. Multiciliogenesis requires activation of a specialized transcription program coupled to complex cytoplasmic events that lead to large-scale centriole amplification to generate multicilia. Yet, it remains unclear how these events are coordinated to initiate multiciliogenesis in epithelial progenitors. Here we identify an unsuspected mechanism orchestrated by the transcription factor E2f4 essential to integrate these processes. We show that after inducing a transcriptional program of centriole biogenesis, E2f4 translocates to the cytoplasm to become a core component of structures classically identified as fibrous granules (FG), acting as organizing centers for deuterosome assembly and centriole amplification. Remarkably, loss of cytoplasmic E2f4 prevents FG aggregation, deuterosome assembly and multicilia formation even when E2f4’s transcriptional function is preserved. Moreover, in E2f4-deficient cells multiciliogenesis is rescued only if both nuclear and cytoplasmic E2f4 activities are restored. Thus, E2f4 integrates previously unrelated nuclear and cytoplasmic events of the multiciliated cell program.
2017-08-30 | GSE73331 | GEO
Project description:The canonical mitotic cell cycle coordinates cell growth, DNA replication, centriole duplication and cytokinesis to generate two cells from one. In certain contexts, such as in mammalian trophoblast giant cells or hepatocytes, cells employ cell cycle variants like the endocycle or endomitosis to increase DNA content without undergoing cytokinesis. Multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tracts, generate hundreds of centrioles during differentiation, each of which extend a motile cilium. We found that multiciliated cells utilize a variant of the cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys much of the mitotic cell cycle regulatory framework, including cell division kinases (CDKs) and cyclins, to generate hundreds of centrioles without undergoing DNA synthesis or cytokinesis. Unlike the mitotic cycle, a transcriptional repressor, E2F7, is upregulated during the multiciliation cycle. E2F7 directly represses genes encoding DNA synthesis machinery during the multiciliation cycle. Loss of E2F7 results in aberrant DNA synthesis and disruption of centriole biogenesis in differentiating multiciliated cells. Thus, multiciliation is coordinated by a variant cell cycle that uses E2F7 to uncouple centriole synthesis from DNA replication.
2024-03-30 | GSE228109 | GEO
Project description:The canonical mitotic cell cycle coordinates cell growth, DNA replication, centriole duplication and cytokinesis to generate two cells from one. In certain contexts, such as in mammalian trophoblast giant cells or hepatocytes, cells employ cell cycle variants like the endocycle or endomitosis to increase DNA content without undergoing cytokinesis. Multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tracts, generate hundreds of centrioles during differentiation, each of which extend a motile cilium. We found that multiciliated cells utilize a variant of the cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys much of the mitotic cell cycle regulatory framework, including cell division kinases (CDKs) and cyclins, to generate hundreds of centrioles without undergoing DNA synthesis or cytokinesis. Unlike the mitotic cycle, a transcriptional repressor, E2F7, is upregulated during the multiciliation cycle. E2F7 directly represses genes encoding DNA synthesis machinery during the multiciliation cycle. Loss of E2F7 results in aberrant DNA synthesis and disruption of centriole biogenesis in differentiating multiciliated cells. Thus, multiciliation is coordinated by a variant cell cycle that uses E2F7 to uncouple centriole synthesis from DNA replication.
2024-03-30 | GSE228108 | GEO
Project description:The canonical mitotic cell cycle coordinates cell growth, DNA replication, centriole duplication and cytokinesis to generate two cells from one. In certain contexts, such as in mammalian trophoblast giant cells or hepatocytes, cells employ cell cycle variants like the endocycle or endomitosis to increase DNA content without undergoing cytokinesis. Multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tracts, generate hundreds of centrioles during differentiation, each of which extend a motile cilium. We found that multiciliated cells utilize a variant of the cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys much of the mitotic cell cycle regulatory framework, including cell division kinases (CDKs) and cyclins, to generate hundreds of centrioles without undergoing DNA synthesis or cytokinesis. Unlike the mitotic cycle, a transcriptional repressor, E2F7, is upregulated during the multiciliation cycle. E2F7 directly represses genes encoding DNA synthesis machinery during the multiciliation cycle. Loss of E2F7 results in aberrant DNA synthesis and disruption of centriole biogenesis in differentiating multiciliated cells. Thus, multiciliation is coordinated by a variant cell cycle that uses E2F7 to uncouple centriole synthesis from DNA replication.
2024-03-30 | GSE245742 | GEO
Project description:The canonical mitotic cell cycle coordinates cell growth, DNA replication, centriole duplication and cytokinesis to generate two cells from one. In certain contexts, such as in mammalian trophoblast giant cells or hepatocytes, cells employ cell cycle variants like the endocycle or endomitosis to increase DNA content without undergoing cytokinesis. Multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tracts, generate hundreds of centrioles during differentiation, each of which extend a motile cilium. We found that multiciliated cells utilize a variant of the cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys much of the mitotic cell cycle regulatory framework, including cell division kinases (CDKs) and cyclins, to generate hundreds of centrioles without undergoing DNA synthesis or cytokinesis. Unlike the mitotic cycle, a transcriptional repressor, E2F7, is upregulated during the multiciliation cycle. E2F7 directly represses genes encoding DNA synthesis machinery during the multiciliation cycle. Loss of E2F7 results in aberrant DNA synthesis and disruption of centriole biogenesis in differentiating multiciliated cells. Thus, multiciliation is coordinated by a variant cell cycle that uses E2F7 to uncouple centriole synthesis from DNA replication.
2024-03-30 | GSE245381 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. The canonical mitotic cell cycle coordinates DNA replication, centriole duplication and cytokinesis to generate two cells from one1. Some cells, such as mammalian trophoblast giant cells, use cell cycle variants like the endocycle to bypass mitosis2. Differentiating multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tract, are post-mitotic but generate hundreds of centrioles, each of which matures into a basal body and nucleates a motile cilium3,4. Several cell cycle regulators have previously been implicated in specific steps of multiciliated cell differentiation5,6. Here we show that differentiating multiciliated cells integrate cell cycle regulators into a new alternative cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys many canonical cell cycle regulators, including cyclin-dependent kinases (CDKs) and their cognate cyclins. For example, cyclin D1, CDK4 and CDK6, which are regulators of mitotic G1-to-S progression, are required to initiate multiciliated cell differentiation. The multiciliation cycle amplifies some aspects of the canonical cell cycle, such as centriole synthesis, and blocks others, such as DNA replication. E2F7, a transcriptional regulator of canonical S-to-G2 progression, is expressed at high levels during the multiciliation cycle. In the multiciliation cycle, E2F7 directly dampens the expression of genes encoding DNA replication machinery and terminates the S phase-like gene expression program. Loss of E2F7 causes aberrant acquisition of DNA synthesis in multiciliated cells and dysregulation of multiciliation cycle progression, which disrupts centriole maturation and ciliogenesis. We conclude that multiciliated cells use an alternative cell cycle that orchestrates differentiation instead of controlling proliferation.
2024-03-29 | GSE228110 | GEO
Project description:Multiciliated cells (MCCs) form when progenitors massively expand centriole number, yielding the hundreds of basal bodies required to extend multiple motile cilia. This organelle biogenesis is promoted transcriptionally by Multicilin acting in a complex with the E2F transcription factors, which activates the expression of genes known to be involved required to form centrioles during the cell cycle, but also requires a cell cycle state required for the centrosome cycle. Multicilin also activates the expression of Emi2 (fbxo43) an inhibitor of the APC/C ubiquitin ligase. In Emi2 mutants, basal body formation during MCCl differentiation is blocked. RNAseq analysis is used to show that gene expression associated with MCC differentiation is upregulated normally in Emi2 mutants, but surprisingly is not downregulated when MCC differentiation is complete. Emi2 is required to promote the centrosomal cycle during MCC differentiation, but then also acts to turn off gene expression associated with centriole biogenesis in differentiated cells.
2024-03-20 | GSE195635 | GEO
Project description:Centriole duplication and DNA replication are two tightly synchronized events of the cell cycle. Perturbations of this coordination lead to genomic instabilities and increased cancer pathologies. Yet, uncoupling of these two molecular events can occur in physiological contexts, such as in post-mitotic multiciliated cell (MCCs) differentiation, during which the activity of the mitotic oscillator is finely tuned to allow centriole amplification while preventing nuclear and cell division. Using single-cell RNA sequencing of MCC-containing tissues, we uncovered that up to 70% of the cell cycle genes are actually co-opted in differentiating MCC progenitors. These progenitors progress through differentiation following a circular transcriptional trajectory characterized by consecutives cell cycle-like phases and successive waves of cyclin expression, mimicking the canonical cell cycle. However, non-canonical cyclins replace cyclins involved in DNA synthesis and mitosis onset, potentially explaining the absence of DNA replication and cell division. Altogether, our results suggest that post-mitotic multiciliated cells have evolved across tissues and mammals by reusing the cell cycle protein toolbox but also the optimality principles of gene expression regulation of the cell cycle, to orchestrate the elaborated stepwise centriole amplification dynamics. This prompts us to propose the existence of a new type of endocycle, where multiciliating cell achieves cytoplasmic organelle amplification rather than ploidy amplification, while still escaping cell division, as in other endocycles.
2025-01-24 | GSE201773 | GEO
Project description:Ependymal cells are multiciliated cells lining the brain ventricles, which arise from the differentiation of progenitor cells through the phases of centriole amplification, growth and disengagement phases. Since these commitment phases are accompanied by the sharp up-regulation of mTOR complex 1 activity (mTORC1), a master regulator of macromolecule biosynthesis and cell growth, we address its functional role. We show that mTORC1 inhibition by rapamycin maintains the progenitor pool by reinforcing a quiescent state and blocking the alternative cell cycle progression for centriole amplification. Overexpression of E2F4 and Mcidas bypasses the mTORC1-regulated events and rescues centriole amplification even in the presence of rapamycin, while promoting mTORC1 activity in a positive feed-forward mechanism. Acute rapamycin treatment in multicentriolar cells during the late phases of differentiation causes centriole regrouping, indicating a direct role of mTORC1 on centriole dynamics. By phosphoproteomic and phospho-mutant analysis, we reveal that the mTORC1-mediated phosphorylation of Gas2L1, a centrosomal protein linking actin and microtubule cytoskeletons, participates in the centriole disengagement. This multi-layered and sequential control of ependymal development by mTORC1, from the progenitor pool to the centriolar function, has implications for pathophysiological conditions, such as aging and hydrocephalus-prone genetic diseases.
2025-03-14 | PXD060982 | Pride
Project description:Multiciliated Ependymal Cells and Adult Neural Stem Cells are components of the adult neurogenic niche, essential for brain homeostasis. These cells share a common glial cell lineage regulated by the Geminin family members Geminin and GemC1/Mcidas. Ependymal precursors require GemC1/Mcidas expression to massively amplify centrioles and become multiciliated cells. Here we show that GemC1-dependent differentiation occurs mostly in cycling Radial Glial Cells, in which a DNA damage response, including replicative stress and dysfunctional telomeres, arrests the cell cycle after the G1/S restriction point due to the activation of the p53-p21 pathway, which contributes to centriole amplification. Telomerase expression in Radial Glial Cells impairs ependymal differentiation and favors the Neural Stem Cell fate.
2021-09-21 | GSE184397 | GEO