Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Multiciliated cells (MCCs), which are present in specialized vertebrate tissues such as mucociliary epithelia, project hundreds of motile cilia from their apical membrane. Coordinated ciliary beating in MCCs contributes to fluid propulsion in several biological processes. In a previous work, we demonstrated that microRNAs of the miR-34/449 family act as new conserved regulators of MCC differentiation by specifically repressing cell cycle genes and the Notch pathway. Recently, we have shown that miR-34/449 also modulate small GTPase pathways to promote, in a later stage of differentiation, the assembly of the apical actin network, a prerequisite for proper anchoring of centrioles-derived neo-synthesized basal bodies. We characterized several miR-34/449 targets related to small GTPase pathways including R-Ras, which represents a key and conserved regulator during MCC differentiation. Direct RRAS repression by miR-34/449 is necessary for apical actin meshwork assembly, notably by allowing the apical relocalization of the actin binding protein Filamin-A near basal bodies. Our studies establish miR-34/449 as central players that orchestrate several steps of MCC differentiation program by regulating distinct signaling pathways.
Figure 1. (A) Schematic description of multiciliogenesis. Proliferating MCC precursors must undergo (1) cell cycle exit followed by (2) the inhibition of BMP and Notch pathways, 2 early events required for the entry into MCC differentiation. (3) In maturing MCCs, the apical actin cytoskeleton is reorganized into a dense cortical meshwork. (4) In addition, a massive multiplication of centrioles occurs, followed by their migration toward the apical membrane, where they mature and anchor to the actin meshwork to form ciliary organizing centers known as basal bodies. (5) Finally, MCC maturation is achieved through the elongation of axonemes from basal bodies to form multiple motile cilia. These motile cilia subsequently orient and beat in a coordinated manner to generate robust directional fluid flow at the surface of the epithelium. (B) Model illustrating the conserved roles of miR-34/449 during vertebrate MCC differentiation. The specific expression of miR-34/449 in immature MCCs allows (1) the exit from the cell cycle and (2) the entry into differentiation through the direct repression of the Notch pathway. As a result, the MCC genetic program is triggered. As miR-34/449 expression is itself repressed by the activation of the Notch signaling, these miRNAs accumulate in maturing MCCs, thus maintaining a double negative feedback loop. Then, miR-34/449 can regulate subsequent steps such as (3) the reorganization of the apical actin network, by directly repressing R-Ras, modulating the RhoA activity, and allowing the apical relocalization of FLNA, and (4) basal body maturation by directly repressing CP110. Plain lines indicate direct interactions; dotted lines identify pathways that may or may not be direct.
Adams,
A meckelin-filamin A interaction mediates ciliogenesis.
2012, Pubmed
Adams,
A meckelin-filamin A interaction mediates ciliogenesis.
2012,
Pubmed
Antoniades,
Making the connection: ciliary adhesion complexes anchor basal bodies to the actin cytoskeleton.
2014,
Pubmed
Bellanger,
The Rac1- and RhoG-specific GEF domain of Trio targets filamin to remodel cytoskeletal actin.
2000,
Pubmed
Boon,
MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.
2014,
Pubmed
,
Xenbase
Boulter,
RhoGDI: A rheostat for the Rho switch.
2010,
Pubmed
Brooks,
Multiciliated cells.
2014,
Pubmed
Burridge,
Rho and Rac take center stage.
2004,
Pubmed
Chevalier,
miR-34/449 control apical actin network formation during multiciliogenesis through small GTPase pathways.
2015,
Pubmed
,
Xenbase
Christodoulou,
Ancient animal microRNAs and the evolution of tissue identity.
2010,
Pubmed
Cibois,
BMP signalling controls the construction of vertebrate mucociliary epithelia.
2015,
Pubmed
,
Xenbase
Comazzetto,
Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 loci.
2014,
Pubmed
Deblandre,
A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos.
1999,
Pubmed
,
Xenbase
Deretic,
Crosstalk of Arf and Rab GTPases en route to cilia.
2013,
Pubmed
Dubaissi,
Embryonic frog epidermis: a model for the study of cell-cell interactions in the development of mucociliary disease.
2011,
Pubmed
,
Xenbase
Epting,
The Rac1 regulator ELMO controls basal body migration and docking in multiciliated cells through interaction with Ezrin.
2015,
Pubmed
Eulalio,
Getting to the root of miRNA-mediated gene silencing.
2008,
Pubmed
Fliegauf,
When cilia go bad: cilia defects and ciliopathies.
2007,
Pubmed
Funk,
Cyclin O (Ccno) functions during deuterosome-mediated centriole amplification of multiciliated cells.
2015,
Pubmed
Gao,
GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells.
2015,
Pubmed
Garcia-Mata,
The 'invisible hand': regulation of RHO GTPases by RHOGDIs.
2011,
Pubmed
Gawecka,
R-Ras regulates migration through an interaction with filamin A in melanoma cells.
2010,
Pubmed
Gomperts,
Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells.
2004,
Pubmed
Griffiths,
R-Ras interacts with filamin a to maintain endothelial barrier function.
2011,
Pubmed
Guilluy,
Rho protein crosstalk: another social network?
2011,
Pubmed
Hansen,
The peripheral olfactory organ of the zebrafish, Danio rerio: an ultrastructural study.
1998,
Pubmed
Huang,
Foxj1 is required for apical localization of ezrin in airway epithelial cells.
2003,
Pubmed
Jeong,
The COOH-terminal end of R-Ras alters the motility and morphology of breast epithelial cells through Rho/Rho-kinase.
2005,
Pubmed
Jerber,
[Transcriptional control of ciliogenesis in animal development].
2012,
Pubmed
Kirchhoff,
HE6/GPR64 adhesion receptor co-localizes with apical and subapical F-actin scaffold in male excurrent duct epithelia.
2008,
Pubmed
Li,
The emerging role of Arf/Arl small GTPases in cilia and ciliopathies.
2012,
Pubmed
Li,
Small GTPases and cilia.
2011,
Pubmed
Liu,
Rho GTPase regulation by miRNAs and covalent modifications.
2012,
Pubmed
Livraghi,
Cystic fibrosis and other respiratory diseases of impaired mucus clearance.
2007,
Pubmed
Malicki,
Analysis of cilia structure and function in zebrafish.
2011,
Pubmed
Marcet,
MicroRNA-based silencing of Delta/Notch signaling promotes multiple cilia formation.
2011,
Pubmed
,
Xenbase
Marcet,
Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway.
2011,
Pubmed
,
Xenbase
Miyatake,
ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled.
2015,
Pubmed
,
Xenbase
Pan,
RhoA-mediated apical actin enrichment is required for ciliogenesis and promoted by Foxj1.
2007,
Pubmed
Park,
Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells.
2008,
Pubmed
,
Xenbase
Shang,
R-Ras and Rac GTPase cross-talk regulates hematopoietic progenitor cell migration, homing, and mobilization.
2011,
Pubmed
Song,
miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110.
2014,
Pubmed
,
Xenbase
Stubbs,
Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation.
2012,
Pubmed
,
Xenbase
Takeda,
Structure and function of vertebrate cilia, towards a new taxonomy.
2012,
Pubmed
Tan,
Myb promotes centriole amplification and later steps of the multiciliogenesis program.
2013,
Pubmed
,
Xenbase
Wallmeier,
Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.
2014,
Pubmed
,
Xenbase
Wang,
miR-34b regulates multiciliogenesis during organ formation in zebrafish.
2013,
Pubmed
Wennerberg,
The Ras superfamily at a glance.
2005,
Pubmed
Wessely,
Xenopus pronephros development--past, present, and future.
2011,
Pubmed
,
Xenbase
Wu,
Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis, and spermatogenesis.
2014,
Pubmed
Zhang,
Molecular views of Arf-like small GTPases in cilia and ciliopathies.
2013,
Pubmed
