Maisonneuve C, Guilleret I, Vick P, Weber T, Andre P, Beyer T et al. Bicaudal C, a novel regulator of Dvl signaling abutting RNA-processing bodies, controls cilia orientation and leftward flow. Development 136: 3019-3030

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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    • "Bicc1 is a mouse homologue of Drosophila Bicaudal-C (dBic-C), the orthologs of which are much conserved in many species, from C. elegans to humans [4], [5], [6], [7], [8]. Loss of dBic-C in Drosophila disrupts the direction of anterior follicle cell migration and affects anterior-posterior patterning, so that the resulting embryos lack heads and exhibit duplicated posterior segments instead [9], [10]. "
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    ABSTRACT: Bicc1 is a mouse homologue of Drosophila Bicaudal-C (dBic-C), which encodes an RNA-binding protein. Orthologs of dBic-C have been identified in many species, from C. elegans to humans. Bicc1-mutant mice exhibit a cystic phenotype in the kidney that is very similar to human polycystic kidney disease. Even though many studies have explored the gene characteristics and its functions in multiple species, the developmental profile of the Bicc1 gene product (Bicc1) in mammal has not yet been completely characterized. To this end, we generated a polyclonal antibody against Bicc1 and examined its spatial and temporal expression patterns during mouse embryogenesis and organogenesis. Our results demonstrated that Bicc1 starts to be expressed in the neural tube as early as embryonic day (E) 8.5 and is widely expressed in epithelial derivatives including the gut and hepatic cells at E10.5, and the pulmonary bronchi at E11.5. In mouse kidney development, Bicc1 appears in the early ureteric bud and mesonephric tubules at E11.5 and is also expressed in the metanephros at the same stage. During postnatal kidney development, Bicc1 expression gradually expands from the cortical to the medullary and papillary regions, and it is highly expressed in the proximal tubules. In addition, we discovered that loss of the Pkd1 gene product, polycystin-1 (PC1), whose mutation causes human autosomal dominant polycystic kidney disease (ADPKD), downregulates Bicc1 expression in vitro and in vivo. Our findings demonstrate that Bicc1 is developmentally regulated and reveal a new molecular link between Bicc1 and Pkd1.
    PLoS ONE 03/2014; 9(3):e88816. DOI:10.1371/journal.pone.0088816 · 3.23 Impact Factor
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    • "They comprise the Kupffer’s vesicle (KV) in bony fish, the gastrocoel roof plate (GRP) of amphibian embryos and the PNC in mammals. Experimental or genetic inhibition of flow, ablation or mispolarization of cilia or impairment of ciliary motility in all cases results in LR axis defects [11,13,17,18]. Downstream of leftward flow, the asymmetric Nodal gene cascade, consisting of the growth factor Nodal, its feedback inhibitor Lefty and the homeobox transcription factor Pitx2, is initiated in the left lateral plate mesoderm (LPM) and governs asymmetric organ morphogenesis and placement at later stages of development [7]. "
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    ABSTRACT: Background: Park2-co-regulated gene (PACRG) is evolutionarily highly conserved from green algae to mammals. In Chlamydomonas and trypanosomes, the PACRG protein associates with flagella. Loss of PACRG results in shortened or absent flagella. In mouse the PACRG protein is required for spermatogenesis. The purpose of the present study was to analyze (1) the expression patterns of PACRG during vertebrate embryogenesis, and (2) whether the PACRG protein was required for left-right (LR) axis specification through cilia-driven leftward flow in Xenopus laevis. Methods: PACRG cDNAs were cloned and expression was analyzed during early embryonic development of Xenopus, mouse, rabbit and zebrafish. Antisense morpholino oligonucleotide (MO) mediated gene knockdown was applied in Xenopus to investigate LR development at the level of tissue morphology, leftward flow and asymmetric marker gene expression, using timelapse videography, scanning electron microscopy (SEM) and whole-mount in situ hybridization. Results were statistically evaluated using Wilcoxon paired and χ2 tests. Results: PACRG mRNA expression was found in cells and tissues harboring cilia throughout the vertebrates. Highly localized expression was also detected in the brain. During early development, PACRG was specifically localized to epithelia where leftward flow arises, that is, the gastrocoel roof plate (GRP) in Xenopus, the posterior notochord (PNC) in mammals and Kupffer’s vesicle (KV) in zebrafish. Besides its association with ciliary axonemes, subcellular localization of PACRG protein was found around the nucleus and in a spotty pattern in the cytoplasm. A green fluorescent protein (GFP) fusion construct preferentially labeled cilia, rendering PACRG a versatile marker for live imaging. Loss-of-function in the frog resulted dose dependently in LR, neural tube closure and gastrulation defects, representing ciliary and non-ciliary functions of PACRG. Conclusions: The PACRG protein is a novel essential factor of cilia in Xenopus.
    08/2012; 1(13). DOI:10.1186/2046-2530-1-13
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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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    ABSTRACT: Most vertebrate embryos break symmetry by a cilia-driven leftward flow during neurulation. In the frog Xenopus asymmetric expression of the ion pump ATP4a was reported at the 4-cell stage. The "ion-flux" model postulates that symmetry is broken flow-independently through an ATP4-generated asymmetric voltage gradient that drives serotonin through gap junctions to one side of the embryo. Here, we show that ATP4a is symmetrically expressed. Gene knockdown or pharmacological inhibition compromised organ situs, asymmetric marker gene expression, and leftward flow. The gastrocoel roof plate (GRP), where flow in frog occurs, revealed fewer, shortened, and misaligned cilia. Foxj1, a master control gene of motile cilia, was downregulated in the superficial mesoderm, from which the GRP develops. Specifically, ATP4 was required for Wnt/β-catenin-regulated Foxj1 induction and Wnt/PCP-dependent cilia polarization. Our work argues for evolutionary conservation of symmetry breakage in the vertebrates.
    Cell Reports 05/2012; 1(5):516-27. DOI:10.1016/j.celrep.2012.03.005 · 8.36 Impact Factor
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