miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110

Song, Rui; Walentek, Peter; Sponer, Nicole; Klimke, Ansgar; Lee, Joon Sub; Dixon, G.L.; Harland, Richard M.; Wan, Ying; Lishko, Polina V.; Lizé, Muriel; Kessel, Michael; He, Lin

doi:10.1038/nature13413

Cited by 195 publications

(286 citation statements)

References 51 publications

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“…During differentiation of mouse and Xenopus MCCs, CP110 expression is repressed by the miR-34/449 microRNA. Inhibition of miR-34/449 induces a defect in ciliogenesis that can be rescued by codepleting CP110, indeed supporting that CP110 function is conserved in MCCs (Song et al 2014).…”

Section: Bb Docking and Ciliary Assemblymentioning

confidence: 67%

Multiciliated Cells in Animals

Meunier¹,

Azimzadeh²

2016

Cold Spring Harb Perspect Biol

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Many animal cells assemble single cilia involved in motile and/or sensory functions. In contrast, multiciliated cells (MCCs) assemble up to 300 motile cilia that beat in a coordinate fashion to generate a directional fluid flow. In the human airways, the brain, and the oviduct, MCCs allow mucus clearance, cerebrospinal fluid circulation, and egg transportation, respectively. Impairment of MCC function leads to chronic respiratory infections and increased risks of hydrocephalus and female infertility. MCC differentiation during development or repair involves the activation of a regulatory cascade triggered by the inhibition of Notch activity in MCC progenitors. The downstream events include the simultaneous assembly of a large number of basal bodies (BBs)-from which cilia are nucleated-in the cytoplasm of the differentiating MCCs, their migration and docking at the plasma membrane associated to an important remodeling of the actin cytoskeleton, and the assembly and polarization of motile cilia. The direction of ciliary beating is coordinated both within cells and at the tissue level by a combination of planar polarity cues affecting BB position and hydrodynamic forces that are both generated and sensed by the cilia. Herein, we review the mechanisms controlling the specification and differentiation of MCCs and BB assembly and organization at the apical surface, as well as ciliary assembly and coordination in MCCs.

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Section: Bb Docking and Ciliary Assemblymentioning

confidence: 67%

Multiciliated Cells in Animals

Meunier¹,

Azimzadeh²

2016

Cold Spring Harb Perspect Biol

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“…Redundancies have also been uncovered among mouse miRNAs. For example, the six mir-34/449 family miRNAs can be individually deleted, resulting in viable and phenotypically normal animals, whereas deletion of all members leads to high postnatal mortality, with surviving animals displaying an array of defects (Fededa et al, 2016;Song et al, 2014). In C. elegans, only 3/15 tested families display abnormalities, suggesting that not all miRNAs with the same seed sequence are redundant.…”

Section: Box 1 Functional Redundancies Among Mirnasmentioning

confidence: 99%

A framework for understanding the roles of miRNAs in animal development

2017

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MicroRNAs (miRNAs) contribute to the progressive changes in gene expression that occur during development. The combined loss of all miRNAs results in embryonic lethality in all animals analyzed, illustrating the crucial role that miRNAs play collectively. However, although the loss of some individual miRNAs also results in severe developmental defects, the roles of many other miRNAs have been challenging to uncover. This has been mostly attributed to their proposed function as tuners of gene expression or providers of robustness. Here, we present a view of miRNAs in the context of development as a hierarchical and canalized series of gene regulatory networks. In this scheme, only a fraction of embryonic miRNAs act at the top of this hierarchy, with their loss resulting in broad developmental defects, whereas most other miRNAs are expressed with high cellular specificity and play roles at the periphery of development, affecting the terminal features of specialized cells. This view could help to shed new light on our understanding of miRNA function in development, disease and evolution.

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“…A critical transcriptional coregulator in this process is multicilin (Mcin or Mcidas), which coordinately controls centriole biogenesis and the assembly of cilia, as well as key transcription factors, such as Myb and forkhead box protein J1 (Foxj1) (12-14). Recent studies have also implicated microRNAs (miRNAs) of the miR-34/449 family in promoting ciliogenesis by suppressing multiple genes, such as Notch1, delta-like 1 (Dll1), and Ccp110, the latter of which is a centriolar protein that inhibits cilia assembly (10,15,16).To identify additional factors regulating mucociliary differentiation, we developed a screen based on a 3D tracheosphere organoid system in which individual basal cells give rise to spheres containing ciliated and secretory luminal cells (4). Our findings revealed IL-6 and the downstream STAT3 pathway as positive regulators of multiciliogenesis.…”

mentioning

confidence: 99%

IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells

Tadokoro

Wang

Barak

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

248

210

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The pseudostratified airway epithelium of the lung contains a balanced proportion of multiciliated and secretory luminal cells that are maintained and regenerated by a population of basal stem cells. However, little is known about how these processes are modulated in vivo, and about the potential role of cytokine signaling between stem and progenitor cells and their niche. Using a clonal 3D organoid assay, we found that IL-6 stimulated, and Stat3 inhibitors reduced, the generation of ciliated vs. secretory cells from basal cells. Gain-offunction and loss-of-function studies with cultured mouse and human basal cells suggest that IL-6/Stat3 signaling promotes ciliogenesis at multiple levels, including increases in multicilin gene and forkhead box protein J1 expression and inhibition of the Notch pathway. To test the role of IL-6 in vivo genetically, we followed the regeneration of mouse tracheal epithelium after ablation of luminal cells by inhaled SO 2 . Stat3 is activated in basal cells and their daughters early in the repair process, correlating with an increase in Il-6 expression in platelet-derived growth factor receptor alpha + mesenchymal cells in the stroma. Conditional deletion in basal cells of suppressor of cytokine signaling 3, encoding a negative regulator of the Stat3 pathway, results in an increase in multiciliated cells at the expense of secretory and basal cells. By contrast, Il-6 null mice regenerate fewer ciliated cells and an increased number of secretory cells after injury. The results support a model in which IL-6, produced in the reparative niche, functions to enhance the differentiation of basal cells, and thereby acts as a "friend" to promote airway repair rather than a "foe."epithelial repair | mucociliary epithelium | cell fate T he conducting airways of the human lung are lined by a pseudostratified epithelium composed of ciliated and secretory cells and basal stem cells. A similar epithelial architecture with basal cells is present in the mouse, although it is limited to the trachea and the largest bronchi. The integrity of this lining is vital for the process of mucociliary clearance by which multiciliated cells move mucus and trapped pathogens and particles out of the lung. Cellular turnover is low in the normal lung, but if luminal cells are destroyed by exposure to toxic compounds or pathogenic agents, the epithelium is rapidly restored from the basal cell population. An example of this injury/repair process is seen in the mouse trachea following exposure to inhaled SO 2 . The surviving p63 + , Keratin-5 (K5) + basal cells quickly spread over the denuded basal lamina and proliferate and regenerate ciliated and secretory cells (1-4). Understanding the mechanisms driving this repair, including the role of factors produced by and acting in the local stem cell niche, may inform strategies to promote recovery after acute respiratory infections or damage by environmental agents. This knowledge may also inform strategies to treat conditions in which the turnover and composition of the air...

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miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110

Cited by 195 publications

References 51 publications

Multiciliated Cells in Animals

Multiciliated Cells in Animals

A framework for understanding the roles of miRNAs in animal development

IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells

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