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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.
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