p53/p21 pathway activation contributes to the ependymal fate decision downstream of GemC1

Ortiz-Álvarez, Gonzalo; Fortoul, Aurélien; Srivastava, Ayush; Moreau, Matthieu; Bouloudi, Benoît; Mailhes-Hamon, Caroline; Delgehyr, Nathalie; Faucourt, Marion; Bahin, Mathieu; Blugeon, Corinne; Bréau, Marielle; Géli, Vincent; Causeret, Frédéric; Meunier, Anne; Spassky, Nathalie

doi:10.1016/j.celrep.2022.111810

Cited by 10 publications

(8 citation statements)

References 66 publications

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“…The observations that HES6 facilitates HSPC maintenance through mediating G1-to-S transition, suggest that HES6 may involve in the functional exhaustion of human HSPCs. Previous studies have demonstrated a strong association between HES6 and the promyelocytic leukemia nuclear body (PML-NB), highlighting its role in modulating cell cycle through the up-regulation the expression of p21 [9], a negative regulator of cell cycle [10]. The current RNA-seq and ChIP-seq data suggested direct regulatory roles for HES6 in positively regulating TFRC and MKI67, two important cell proliferation mediators, in a GATA1 independent manner.…”

mentioning

confidence: 68%

HES6: an emerging player in human hematopoiesis

Xu,

2024

haematol

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confidence: 68%

HES6: an emerging player in human hematopoiesis

Xu,

2024

haematol

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“…Our results thus show that mechanical constraints on the nucleus are important for EC differentiation in the mouse brain. Accordingly, to this nuclear stress on ependymal progenitors, Lamin-A at the nuclear envelope (Fig.6C, S5D) and DNA-damage increase 34,47 .…”

Section: Discussionmentioning

confidence: 90%

“…In cycling cells, CDK2 is known to phosphorylate retinoblastoma protein (RB1), triggering the release of E2F transcription factors from their interaction with RB1 and allowing them to activate S-phase specific genes to transition out of G1 33 . In ependymal cells, we know from previous work that CDK2 is required for the early steps of multiciliated differentiation 11,34 and that RB1 is hyperphosphorylated in differentiating EC 34 .…”

Section: S-phase Transition Factors Are Downstream Of Nuclear Deforma...mentioning

confidence: 98%

Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation

Basso,

Mahuzier,

Ali

et al. 2023

Preprint

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Ependymal cells (ECs) are multi-ciliated cells in the brain that contribute to cerebrospinal fluid flow. ECs are specified at embryonic stages but differentiate and grow cilia later in development. Differentiation depends on genes such as GEMC1 and MCIDAS with E2F4/5 but also on cell cycle related factors. In the mouse brain, we observe that nuclear deformation accompanies EC differentiation. Tampering with these deformations either by decreasing F-actin levels or by severing the link between the nucleus and the actin cytoskeleton blocks differentiation. Conversely, increasing F-actin by knocking out the Arp2/3 complex inhibitor Arpin activates differentiation. Thus, actin polymerization triggers nuclear deformation and jump-starts the signaling that produce differentiated ECs. We show evidence that one of the players in this process is the retinoblastoma 1 (RB1) protein whose phosphorylation prompts MCIDAS activation. Overall, this study reveals an important role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.

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“…4C and D ). We also stained WT and Cena KO cultures for retinoblastoma protein phosphorylation (pRB pSer807/811), another hallmark of cycling cells entering S-phase (Zhou et al, 2022), which was recently shown to also turn positive during early MCC differentiation (Basso et al, 2023; Ortiz-Alvarez et al, 2022). Consistent with the p27 observations, while the proportion of pRB+ cells begins to increase in FOXJ1+ WT cells entering A-stage (:: 26%), very few cells are pRB+ in FOXJ1+ Cena KO cells (:: 3%), a proportion comparable to the proportion observed in WT FOXJ1+ cells at the centrosome stage (:: 4%) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

Damaa,

Serizay,

Balagué

et al. 2024

Preprint

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Multiciliated cells (MCC) ensure proper fluid circulation in various organs in metazoans. Their differentiation is marked by the massive amplification of cilia-nucleating centrioles and is known to be controlled by various cell cycle components. In a companion study, we show that the differentiation of MCC is driven by a genuine cell-cycle variant characterized by sequential and wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of Primary Ciliary Dyskinesia (PCD) designated as Reduced Generation of Multiple Motile Cilia (RGMC), yet the role of CCNO during MCC differentiation remains unclear. Here, using mice and human cellular models, single cell transcriptomics and functional studies, we show that Ccno is activated during a strategic temporal window at the crossroads between the onset of MCC differentiation, the entry into the MCC cell cycle variant, and the activation of the centriole biogenesis program. We find that the absence of Ccno leads to a block of MCC progenitor differen- tiation at the G1/S-like transition, just before the beginning of centriole formation. This leads to a complete lack of centrioles and cilia in mouse brain and human airway MCC. Altogether, our study identifies CCNO as a core regulator of entry into the MCC cell cycle variant and shows that the coupling of centriole biogenesis to an S-like phase, maintained in MCC, is dependent on CCNO.

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p53/p21 pathway activation contributes to the ependymal fate decision downstream of GemC1

Cited by 10 publications

References 66 publications

HES6: an emerging player in human hematopoiesis

HES6: an emerging player in human hematopoiesis

Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

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