Divergent roles for Wnt/ -catenin signaling in epithelial maintenance and breakdown during semicircular canal formation

Development (Impact Factor: 6.46). 03/2013; 140(8). DOI: 10.1242/dev.092882
Source: PubMed


The morphogenetic program that shapes the three semicircular canals (SSCs) must be executed with extreme precision to satisfy their complex vestibular function. The SSCs emerge from epithelial outgrowths of the dorsal otocyst, the central regions of which fuse and resorb to leave three fluid-filled canals. The Wnt/_-catenin signaling pathway is active at multiple stages of otic development, including during vestibular morphogenesis. How Wnt/_-catenin functionally integrates with other signaling pathways to sculpt the SSCs and their sensory patches is unknown. We used a genetic strategy to spatiotemporally modulate canonical Wnt signaling activity during SSC development in mice. Our findings demonstrate that Wnt/_-catenin signaling functions in a multifaceted manner during SSC formation. In the early phase, Wnt/_-catenin signaling is required to preserve the epithelial integrity of the vertical canal pouch perimeter (presumptive anterior and posterior SSCs) by establishing a sensory-dependent signaling relay that maintains expression of Dlx5 and opposes expression of the fusion plate marker netrin 1. Without this Wnt signaling activity the sensory to non-sensory signaling cascade fails to be activated, resulting in loss of vestibular hair and support cells and the anterior and posterior SSCs. In the later phase, Wnt/_-catenin signaling becomes restricted to the fusion plate where it facilitates the timely resorption of this tissue. Mosaic recombination of _-catenin in small clusters of canal pouch cells prevents their resorption, causing instead the formation of ectopic SSCs. Together, these disparate functions of the Wnt/_-catenin pathway in epithelial maintenance and resorption help regulate the size, shape and number of SSCs.

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    • "Serial homology can nowadays be understood as a type of intraorganismal homology, with repetitive features sharing a large proportion of their genetic architecture and developmental pathways (Harris et al. 2003; Young and Hallgrímsson 2005; Gómez-Robles and Polly 2012). According to this definition, the semicircular canals may well be serial homologues as they share a large part of their genetic and developmental pattern (Bok et al. 2007; Chang et al. 2008; Rakowiecki and Epstein 2013). This is why we tested the independence of similar continuous variables measured on different canals. "
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    ABSTRACT: We present a survey of the morphological diversity of the bony labyrinth of the inner ear in Xenarthra, including the fossil ground sloth Megatherium. Using a combination of traditional and geometric morphometrics, correlation analyses, and qualitative observations, we attempt to extract independent and informative phylogenetic characters of the bony labyrinth for the superorder. Geometric morphometric analyses demonstrate a strong imprint of phylogenetic history on the shape of the bony labyrinth of xenarthrans and a weak influence of allometry. Discrete characters mapped on a consensus cladogram for xenarthrans show support for many traditional nodes within the superorder and may also provide critical information for problematic nodes within Cingulata. A relatively large lateral semicircular canal may, for instance, represent a synapomorphy for the molecular clade allying fairy armadillos (Chlamyphorinae) to the Tolypeutinae. Striking convergences were detected when comparing Megatherium, the giant ground sloth, with extant armadillos and Chlamyphorus, the pink fairy armadillo, with the extant three- and two-toed sloths. These findings have the potential to help understand the phylogenetic relationships of fossil xenarthrans.
    Journal of Mammalogy 08/2015; 96(4). DOI:10.1093/jmammal/gyv074 · 1.84 Impact Factor
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    • "The Wnt/β-catenin signaling pathway is reported to play important roles in mammalian cochlear development and hair cell regeneration by regulating both proliferation and differentiation of prosensory cells. The Wnt/β-catenin signaling pathway is also critical for otocyst induction, dorsal patterning of the otocyst, and the eventual formation of the vestibular organs (Hollyday et al., 1995; Jasoni et al., 1999; Riccomagno et al., 2005; Lillevali et al., 2006; Ohyama et al., 2006; Rakowiecki and Epstein, 2013). Wnt/β-catenin signaling also plays a key role in hair cell formation in the cochlea, and this is clearly demonstrated by the inability of hair cells to differentiate from sensory progenitors when Wnt/β-catenin is knocked out (Jacques et al., 2012; Shi et al., 2014). "
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    ABSTRACT: The Wnt/β-catenin signaling pathway plays important roles in mammalian inner ear development. Lgr5, one of the downstream target genes of the Wnt/β-catenin signaling pathway, has been reported to be a marker for inner ear hair cell progenitors. Lgr6 shares approximately 50% sequence homology with Lgr5 and has been identified as a stem cell marker in several organs. However, the detailed expression profiles of Lgr6 have not yet been investigated in the mouse inner ear. Here, we first used Lgr6-EGFP-Ires-CreERT2 mice to examine the spatiotemporal expression of Lgr6 protein in the cochlear duct during embryonic and postnatal development. Lgr6-EGFP was first observed in one row of prosensory cells in the middle and basal turn at embryonic day 15.5 (E15.5). From E18.5 to postnatal day 3 (P3), the expression of Lgr6-EGFP was restricted to the inner pillar cells (IPCs). From P7 to P15, the Lgr6-EGFP expression level gradually decreased in the IPCs and gradually increased in the inner border cells (IBCs). At P20, Lgr6-EGFP was only expressed in the IBCs, and by P30 Lgr6-EGFP expression had completely disappeared. Next, we demonstrated that Wnt/β-catenin signaling is required to maintain the Lgr6-EGFP expression in vitro. Finally, we demonstrated that the Lgr6-EGFP-positive cells isolated by flow cytometry could differentiate into myosin 7a-positive hair cells after 10 days in-culture, and this suggests that the Lgr6-positive cells might serve as the hair cell progenitor cells in the cochlea.
    Frontiers in Cellular Neuroscience 05/2015; 9. DOI:10.3389/fncel.2015.00165 · 4.29 Impact Factor
    • "When the sides of the canal pouches (in amniotes) or tips of the projections (in zebrafish and Xenopus) touch each other, cells change behaviour to form a fusion plate. Establishment of the zones of fusion and non-fusion in the mouse ear involves an antagonistic interaction between Lrig3 and Netrin1 (Salminen et al., 2000; Abraira et al., 2008), and regulation by Wnt signalling (Noda et al., 2012; Rakowiecki and Epstein, 2013). Resolution at the fusion plate in mouse, chick and Xenopus involves breakdown of the basal lamina (Haddon and Lewis, 1991; Salminen et al., 2000; Abraira et al., 2008), epithelial-to-mesenchymal transition (Salminen et al., 2000; Kobayashi et al., 2008) and cell death (Haddon and Lewis, 1991; Fekete et al., 1997; Cecconi et al., 2004). "
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    ABSTRACT: Morphogenesis of the semicircular canal ducts in the vertebrate inner ear is a dramatic example of epithelial remodelling in the embryo, and failure of normal canal development results in vestibular dysfunction. In zebrafish and Xenopus, semicircular canal ducts develop when projections of epithelium, driven by extracellular matrix production, push into the otic vesicle and fuse to form pillars. We show that in the zebrafish, extracellular matrix gene expression is high during projection outgrowth and then rapidly downregulated after fusion. Enzymatic disruption of hyaluronan in the projections leads to their collapse and a failure to form pillars: as a result, the ears swell. We have cloned a zebrafish mutant, lauscher (lau), identified by its swollen ear phenotype. The primary defect in the ear is abnormal projection outgrowth and a failure of fusion to form the semicircular canal pillars. Otic expression of extracellular matrix components is highly disrupted: several genes fail to become downregulated and remain expressed at abnormally high levels into late larval stages. The lau mutations disrupt gpr126, an adhesion class G protein-coupled receptor gene. Expression of gpr126 is similar to that of sox10, an ear and neural crest marker, and is partially dependent on sox10 activity. Fusion of canal projections and downregulation of otic versican expression in a hypomorphic lau allele can be restored by cAMP agonists. We propose that Gpr126 acts through a cAMP-mediated pathway to control the outgrowth and adhesion of canal projections in the zebrafish ear via the regulation of extracellular matrix gene expression.
    Development 09/2013; 140(21). DOI:10.1242/dev.098061 · 6.46 Impact Factor
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