Bicaudal C, a novel regulator of Dvl signaling abutting RNA-processing bodies, controls cilia orientation and leftward flow

Ecole Polytechnique Fédérale de Lausanne, Station 19, Lausanne, Switzerland.
Development (Impact Factor: 6.27). 10/2009; 136(17):3019-30. DOI: 10.1242/dev.038174
Source: PubMed

ABSTRACT Polycystic diseases and left-right (LR) axis malformations are frequently linked to cilia defects. Renal cysts also arise in mice and frogs lacking Bicaudal C (BicC), a conserved RNA-binding protein containing K-homology (KH) domains and a sterile alpha motif (SAM). However, a role for BicC in cilia function has not been demonstrated. Here, we report that targeted inactivation of BicC randomizes left-right (LR) asymmetry by disrupting the planar alignment of motile cilia required for cilia-driven fluid flow. Furthermore, depending on its SAM domain, BicC can uncouple Dvl2 signaling from the canonical Wnt pathway, which has been implicated in antagonizing planar cell polarity (PCP). The SAM domain concentrates BicC in cytoplasmic structures harboring RNA-processing bodies (P-bodies) and Dvl2. These results suggest a model whereby BicC links the orientation of cilia with PCP, possibly by regulating RNA silencing in P-bodies.

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Available from: Martin Blum, Jan 18, 2014
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    • "Polarization defects of GRP cilia (cf. Figures 2H and 2K) likely represent Wnt defects as well, as it has recently been shown that noncanonical Wnt signaling controls posterior polarization of LR cilia in mouse and frog (Maisonneuve et al., 2009; Antic et al., 2010; Song et al., 2010). A link between Wnt signaling and another proton pump, the vacuolar H + -ATPase (ATP6), has been recently established, in which acidification of Wnt signalosomes was shown to be crucial for both canonical and noncanonical Wnt signaling (Cruciat et al., 2010; Hermle et al., 2010). "
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    Cell Reports 05/2012; 1(5):516-27. DOI:10.1016/j.celrep.2012.03.005 · 7.21 Impact Factor
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    • "As a last control experiment we analyzed flow directly, as impaired cilia motility would have resulted in the observed LR phenotypes as well. Dorsal explants of wildtype (n55) or Cx26-MO (n58) injected neurula embryos were prepared, fluorescent beads were added and flow was analyzed by time-lapse videography as described (Maisonneuve et al., 2009; Vick et al., 2009). Flow in morphants was indistinguishable from uninjected specimens (data not shown). "
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    05/2012; 1(5):473-81. DOI:10.1242/bio.2012760
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    • "Our finding that Dvl2 K446M mutant is functionally defective in regulating SG dynamics (Fig. 1D,E) raises the exciting possibility that the PCP defect in dsh 1 mutant (Boutros and Mlodzik, 1999) could, at least in part, be due to defective mRNA functions. Two recent reports further support a function for Dvl in mRNA regulation (Bikkavilli and Malbon, 2010; Maisonneuve et al., 2009). "
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    ABSTRACT: Cells often respond to diverse environmental stresses by inducing stress granules (SGs) as an adaptive mechanism. SGs are generally assembled as a result of aggregation of mRNAs stalled in a translational pre-initiation complex, mediated by a set of RNA-binding proteins such as G3BP and TIA-1. SGs may serve as triage centres for storage, translation re-initiation or degradation of specific mRNAs. However, the mechanism involved in the modulation of their assembly/disassembly is unclear. Here we report that Wnt signalling negatively regulates SG assembly through Dishevelled (Dvl), a cytoplasmic Wnt effector. Overexpression of Dvl2, an isoform of Dvl, leads to impairment of SG assembly through a DEP domain dependent mechanism. Intriguingly, the Dvl2 mutant K446M, which corresponds to an analogous mutation in Drosophila Dishevelled DEP domain (dsh(1)) that results in defective PCP pathway, fails to antagonize SG assembly. Furthermore, we show that Dvl2 exerts the antagonistic effect on SG assembly through a mechanism involving Rac1-mediated inhibition of RhoA. Dvl2 interacts with G3BP, a downstream component of Ras signalling involved in SG assembly, and functional analysis suggests a model wherein the Dvl-Rac1-RhoA axis regulates G3BP's SG-nucleating activity. Collectively, these results define an antagonistic effect of Wnt signalling on SG assembly, and reveal a novel role for Wnt/Dvl pathway in the modulation of mRNA functions.
    02/2012; 1(2):109-19. DOI:10.1242/bio.2011023
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