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.

19 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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. Presentamos un estudio de la diversidad morfol o ´ gica del laberinto o ´ seo del o i ´ do interno de los xenartros, incluyendo el perezoso f o ´ sil Megatherium . Utilizamos una combinaci o ´ n de morfom e ´ trica tradicional y geom e ´ trica, an a ´ lisis de correlaci o ´ n y observaciones cuantitativas para intentar extraer caracteres filogen e ´ ticos independientes e informativos del laberinto o ´ seo para el superorden. Los an a ´ lisis geom e ´ tricos morfom e ´ tricos muestran una fuerte impronta de la historia filogen e ´ tica de la forma del laberinto o ´ seo de los xenartros y una baja influencia de la alometr i ´ a. Los caracteres discretos mapeados en un cladograma de consenso para xenartros apoyan varios nodos tradicionales dentro del superorden y podr i ´ an tambi e ´ n brindar informaci o ´ n importante para los nodos problem a ´ ticos dentro de los Cingulata. Un canal semicircular lateral relativamente largo podr i ´ a, por ejemplo, representar una sinapomorf i ´ a que apoye el clado molecular que une a los pichiciegos con los Tolypeutinae. Se hallaron notables convergencias al comparar Megatherium con los armadillos actuales, y Chlamyphorus con los perezosos actuales. Estos hallazgos tienen el potencial para ayudar a entender las relaciones filogen e ´ ticas de los xenartros f o ´ siles.
    Journal of Mammalogy 08/2015; 96(4). DOI:10.1093/jmammal/gyv074 · 1.84 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). "
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of hair cells in the auditory system can be separated into steps; first, the establishment of progenitors for the sensory epithelium, and second, the differentiation of hair cells. Although the differentiation of hair cells is known to require the expression of basic helix-loop-helix transcription factor, Atoh1, the control of cell proliferation in the region of the developing cochlea that will ultimately become the sensory epithelium and the cues that initiate Atoh1 expression remain obscure. We assessed the role of Wnt/β-catenin in both steps in gain- and loss-of-function models in mice. The canonical Wnt pathway mediator, β-catenin, controls the expression of Atoh1. Knock-out of β-catenin inhibited hair-cell, as well as pillar-cell, differentiation from sensory progenitors but was not required to maintain a hair-cell fate once specified. Constitutive activation of β-catenin expanded sensory progenitors by inducing additional cell division and resulted in the differentiation of extra hair cells. Our data demonstrate that β-catenin plays a role in cell division and differentiation in the cochlear sensory epithelium.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2014; 34(19):6470-9. DOI:10.1523/JNEUROSCI.4305-13.2014 · 6.34 Impact Factor
Show more