XB-ART-47874
Development
November 1, 2013;
140
(21):
4362-74.
Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene.
Geng FS
,
Abbas L
,
Baxendale S
,
Holdsworth CJ
,
Swanson AG
,
Slanchev K
,
Hammerschmidt M
,
Topczewski J
,
Whitfield TT
.
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.
PubMed ID: 24067352
PMC ID: PMC4007713
Article link: Development
Grant support: [+]
084551 Wellcome Trust , BB/J003050 Biotechnology and Biological Sciences Research Council , G0300196 Medical Research Council , G0400100 Medical Research Council , G0700091 Medical Research Council , GR077544AIA Medical Research Council , GR077544AIA Wellcome Trust , BB/J003050/1 Biotechnology and Biological Sciences Research Council
Species referenced: Xenopus laevis
Genes referenced: adgrg6 aldh1a3 bmp4 c1s chsy1 dnai1 foxd3 foxi1 fubp1 galnt14 gprc6a hapln3 has3 hbd kcnq1 slc12a2 slc25a27 sox10 ugdhl vcan
Article Images: [+] show captions
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Fig. 1. Semicircular canal morphogenesis in the zebrafish ear. (A-F) Sketches of the developing semicircular canal system in the wild-type zebrafish ear, showing projection outgrowth, fusion and pillar formation. (G-L) Expression of vcana in the wild-type ear. (A,G) At 48 hpf, both anterior (A) and posterior (P) projections have begun to grow, and to express vcana at their tips. (B,H) The lateral projection, with its A and P bulges, is present by 50 hpf. The bulges and projections express vcana strongly at this time. The apparent downward growth of the A projection in H may be an artefact of fixation. (C,I) From 57-68 hpf, the A and P projections and bulges fuse to form the A and P pillars. The lateral projection now forms a ventral (V) bulge, and a V projection develops. Expression of vcana is downregulated in the A and P pillars, but is now strongly expressed in the V bulge and projection. (D,J) As fusion is completed at ∼70 hpf, expression of vcana is downregulated in all pillars. Expression remains in the dorsolateral septum (DLS) at 84 hpf. (E,K) At 72 hpf, all three pillars are fused [timing of fusion was slightly later than previously reported (Waterman and Bell, 1984)]. (F,L) At 4-5 dpf, only a trace of vcana expression remains in the DLS. Grey shading indicates the canal lumens. The positions of the cristae are shown. Abbreviations: A, anterior; DLS, dorsolateral septum; P, posterior; proj., projection; ssc, semicircular canal; V, ventral. Scale bar: 50 μm. |
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Fig. 3. Expression of genes involved in endolymph homeostasis in the lau mutant ear. (A-D) The endolymphatic duct, marked by expression of bmp4 (arrowheads, A,B) and foxi1 (C,D), appears to develop normally in lau mutants. The three cristae also express bmp4 normally (asterisks, A,B). (E-J) Expression of ion transporter genes in the lau mutant ear. (E,F) Expression of the atp1a1a.4 subunit of Na+/K+-ATPase1 is more diffuse and lacking from the ventral pillar (vp). (G-J) There is a substantial reduction in both kcnq1 and nkcc1 expression. Abbreviation: vp, ventral pillar (E) or ventral projection (F). Alleles: B,D,H,J, tk256a; F, tb233c. Scale bars: 50 μm. |
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Fig. 4. Expression of extracellular matrix (ECM) genes and other semicircular canal markers is altered in the lauscher mutant ear. (A-JJ) Expression of ECM structural and enzyme genes in lau mutant ears at 76 hpf, 4 dpf and 5 dpf. Expression of the HA binding hapln1a (A-F) and the versican genes vcana and vcanb (M-X) is highly upregulated in mutant canal tissue. Expression of hapln3 is normally upregulated in wild-type ears on canal projection fusion (G,I,K); in the mutant, fusion fails, and transcript levels remain low (H,J,L). Antibody staining for type II Collagen (Y-DD) shows precocious protein accumulation at 76 hpf in mutants (Y,Z), persisting at 4-5 dpf (AA-DD); aberrant canal tissue is visible. Genes coding for enzymes for chondroitin synthesis (chsy1, EE,FF) and HA production (has3, GG,HH; ugdh, II,JJ) are upregulated in mutants at 76 hpf. (KK-PP) The canal markers aldh1a3, bmp7b and sox9b are upregulated in the unfused projections in the lau mutant ear. wt, wild type; sib, phenotypically wild-type sibling. Mutant alleles are shown on the panels. Scale bars: in A, 50 μm (applies to columns 1 and 2); in C, 50 μm (applies to all other panels). |
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Fig. 5. Positional cloning, identification and confirmation of mutations in gpr126. (A) Genetic map of the lau locus. Numbers of meiotic recombinants for the flanking SSLP markers and SNP markers in slc25a27, schnurri2 and galnt14 are shown. (B) Sequence analysis of gpr126 cDNA in wild type (upper panels) and lau mutants (lower panels), with predicted changes to the coding sequence. (C) Schematic diagram of the Gpr126 protein, with its conserved domains: CUB (Complement C1r/C1s, Uegf, BMP1), PTX (Pentraxin), HBD (hormone binding domain), GAIN (GPCR autoproteolysis inducing) domain, GPS (GPCR proteolytic site) motif and 7TM (7-transmembrane) domain (not to scale). Positions of the mutations are shown. (D) Amino acid comparison of the fourth transmembrane (TMIV) region from eight zebrafish adhesion class GPCRs, showing the conserved hydrophobic residue at position 963 (mutated in tb233c), and the highly conserved proline (P) at position 969 (mutated in tk256a) (asterisks). (E) Genotyping of lau mutant fish by restriction digest of PCR-amplified genomic DNA. In tb233c, the mutation eliminated an SfaN1 site; in tk256a, the mutation eliminated a BsmF1 site; in the fr24 allele, a Bfa1 site was gained. (F,G) gpr126 morpholino injection recapitulates the lau mutant ear phenotype. (F) Wild-type (nac) embryos (left hand panels) injected with 5 ng control morpholino exhibit normal ear morphology at 5 dpf (a,c), and low vcanb expression at 5 dpf (e). Wild-type (nac) embryos injected with 5 ng gpr126 morpholino (right hand panels) have abnormal projection outgrowth (b,d). The lateral projection (lp) is enlarged, and the posterior projection (pp) in this ear has grown past the lateral projection without fusing. Expression of vcanb is upregulated (f). (G) RT-PCR analysis of gpr126 mRNA processing of the 19th exon in gpr126 morpholino-injected, or in control (mismatched) morpholino-injected, embryos at 5 dpf. Sequencing confirmed two aberrant splice variants. Panels c,d are dorsal views, anterior towards the top. Scale bars: 200 μm in a,b; 50 μm in c,d; 50 μm in e,f. |
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Fig. 6. Expression of gpr126 in wild-type and lauscher mutant ears. (A-H) Expression of gpr126 mRNA in the ear at 24-96 hpf in wild-type (A-D) and fr24 mutant embryos (E-H). Strongest expression is in canal projections prior to fusion (48-72 hpf), with some expression remaining at 96 hpf. Inset in D: higher magnification showing expression in the anterior macula supporting cell layer. (I,M) Wild-type expression of gpr126 at 26 hpf in the anterior macula (I, dorsal view; M, transverse section). (J,N) Expression at 48 hpf shows stronger staining in the projections and sensory patches (J, dorsal view; N, transverse section). (K) Expression in sensory patches at 72 hpf is restricted to supporting cells (arrowhead) (transverse section; see also inset in D). There is strong expression in the projections. (L) Alternative focus view of D, showing residual expression in the lateral projection at 96 hpf. (O,P) Expression of gpr126 (blue) and vcanb (red) in the projections of wild-type and fr24 mutant embryos at 65 hpf. In wild-type embryos (O), there is co-expression (purple) in the recently fused ventral pillar; vcanb is downregulated in the lateral projection and in the anterior and posterior pillars (out of focus), whereas gpr126 is expressed at reduced levels. In fr24 mutants (P), vcanb and gpr126 are co-expressed in the unfused projections. Expression of vcanb persists in the dorsolateral septum, which does not express gpr126, in both wild-type and mutant embryos (O, arrow). Scale bars: in A, 50 μm for A-C,E-G,M,O,P; 50 μm in D,H,L; 25 μm in K; 100 μm in I,J,N. |
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Fig. 7. Comparison of expression of gpr126 and sox10 in wild-type embryos, and expression of gpr126 in colourless (sox10-/-) mutant embryos. (A-D) Expression of gpr126 and sox10 in wild-type embryos at 24 hpf (A,B) and 48 hpf (C,D). Both genes are expressed in the otic vesicle (arrowhead), post-otic region (arrow), olfactory epithelium (nose, n) and head chondrocytes (asterisks). (E-G) Dorsal views of flat-mounted 24 hpf embryos: post-otic expression of gpr126 in the wild type (E) is lost in the cls mutant (F). Comparison with foxd3 expression identifies these cells as neural crest (G). (H,I) Dorsal view of the post-otic region showing foxd3-expressing Schwann cells extending posteriorly (H, arrow) and expression of gpr126 in the same location (I, arrow). (J,K) gpr126 expression in heart (h) and posterior mesoderm (m) persists in cls mutants, whereas neural crest expression is lost (arrows). (L,M) Expression of gpr126 is reduced in the cls mutant ear at 48 hpf, with weak expression in rudimentary projections (M). (N,O) DIC images of live ears at 96 hpf, showing a representative cls mutant ear (O). Note the small overall size and rudimentary unfused canal projections (arrowheads). Abbreviations: h, heart; m, posterior mesoderm, n, nose (olfactory epithelium); nc, neural crest; ov, otic vesicle; sib, phenotypically wild-type sibling embryo. Scale bars: in D, 100 μm for A-D; in G, 50 μm for to E-G; in I, 50 μm for H,I; in K, 100 μm for J,K; in L, 50 μm for L-O. |
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Fig. 8. Treatment with cAMP agonists rescues the lauscher ear phenotype. (A-X) Live images at 5 dpf in control and drug-treated embryos. Ear swelling in tb233c mutants was variable, and categorized as ‘mild’ (E-H) or ‘severe’ (I-L) compared with wild type (A-D). Arrowhead in D indicates fused pillar in the untreated wild-type ear. Treatment between 60 and 90 hpf with cAMP agonists forskolin (25 μM; Q-T) and IBMX (100 μM; U-X) rescues the swollen ear phenotype; DMSO has no effect (M-P). Fusion of the anterior (a), posterior (p) and ventral (v) projections to form pillars is also restored: rescued pillars are present in drug-treated embryos (R,V; arrowheads in T,X) but not in DMSO-treated samples (N,P). However, small, ectopic tissue protrusions are present on the rescued pillars (asterisks, T,X). (Y-BB) Both drugs (forskolin, 50 μM; IBMX, 100 μM) can reduce expression of vcan genes in the ear (Y-BB). (CC) Graphical representation of the ear swelling data, analysed with a 3×3 (DMSO, forskolin) or 3×4 (DMSO, IBMX) chi-square contingency table; P<0.001 (both drugs). n values are in parentheses. (C,G,K,O,S,W) Dorsal views. |
References [+] :
Abbas,
Nkcc1 (Slc12a2) is required for the regulation of endolymph volume in the otic vesicle and swim bladder volume in the zebrafish larva.
2009, Pubmed
Abbas,
Nkcc1 (Slc12a2) is required for the regulation of endolymph volume in the otic vesicle and swim bladder volume in the zebrafish larva.
2009,
Pubmed
Abraira, Cross-repressive interactions between Lrig3 and netrin 1 shape the architecture of the inner ear. 2008, Pubmed
Acampora, Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. 1999, Pubmed
Araç, A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. 2012, Pubmed
Asai, Mutation of the atrophin2 gene in the zebrafish disrupts signaling by fibroblast growth factor during development of the inner ear. 2006, Pubmed
Babb-Clendenon, Cadherin-2 participates in the morphogenesis of the zebrafish inner ear. 2006, Pubmed
Bahary, The Zon laboratory guide to positional cloning in zebrafish. 2004, Pubmed
Bakkers, Has2 is required upstream of Rac1 to govern dorsal migration of lateral cells during zebrafish gastrulation. 2004, Pubmed , Xenbase
Bissonnette, Standard atlas of the gross anatomy of the developing inner ear of the chicken. 1996, Pubmed
Bjarnadóttir, The adhesion GPCRs: a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues. 2007, Pubmed
Bjarnadóttir, The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. 2004, Pubmed
Blasiole, Neuronal calcium sensor-1 gene ncs-1a is essential for semicircular canal formation in zebrafish inner ear. 2005, Pubmed
Blasiole, Separate Na,K-ATPase genes are required for otolith formation and semicircular canal development in zebrafish. 2006, Pubmed
Bok, Patterning and morphogenesis of the vertebrate inner ear. 2007, Pubmed
Brösamle, Characterization of myelination in the developing zebrafish. 2002, Pubmed
Busch-Nentwich, The deafness gene dfna5 is crucial for ugdh expression and HA production in the developing ear in zebrafish. 2004, Pubmed
Cantos, Patterning of the mammalian cochlea. 2000, Pubmed
Carney, Genetic analysis of fin development in zebrafish identifies furin and hemicentin1 as potential novel fraser syndrome disease genes. 2010, Pubmed
Cecconi, Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth. 2004, Pubmed
Chang, Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements. 2008, Pubmed
Chang, The development of semicircular canals in the inner ear: role of FGFs in sensory cristae. 2004, Pubmed
Chen, Functions of hyaluronan in wound repair. 1999, Pubmed
Chiang, Two sox9 genes on duplicated zebrafish chromosomes: expression of similar transcription activators in distinct sites. 2001, Pubmed
Cruz, Plasma membrane calcium ATPase required for semicircular canal formation and otolith growth in the zebrafish inner ear. 2009, Pubmed
Deng, Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear. 2010, Pubmed
Dutton, A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. 2009, Pubmed
Dutton, Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. 2001, Pubmed
Elks, A role for soluble cAMP phosphodiesterases in differentiation of 3T3-L1 adipocytes. 1985, Pubmed
Enomoto, Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. 2010, Pubmed
Everett, Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. 2001, Pubmed
Fekete, Involvement of programmed cell death in morphogenesis of the vertebrate inner ear. 1997, Pubmed
Fritzsch, Otx1 null mutant mice show partial segregation of sensory epithelia comparable to lamprey ears. 2001, Pubmed
Glenn, Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin. 2013, Pubmed , Xenbase
Haddon, Hyaluronan as a propellant for epithelial movement: the development of semicircular canals in the inner ear of Xenopus. 1992, Pubmed , Xenbase
Haddon, Early ear development in the embryo of the zebrafish, Danio rerio. 1996, Pubmed
Hadrys, Nkx5-1 controls semicircular canal formation in the mouse inner ear. 1998, Pubmed
Hammerschmidt, Genetic analysis of dorsoventral pattern formation in the zebrafish: requirement of a BMP-like ventralizing activity and its dorsal repressor. 1996, Pubmed
Hammond, Repression of Hedgehog signalling is required for the acquisition of dorsolateral cell fates in the zebrafish otic vesicle. 2010, Pubmed
Hammond, The developing lamprey ear closely resembles the zebrafish otic vesicle: otx1 expression can account for all major patterning differences. 2006, Pubmed
Han, Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28. 2011, Pubmed
Hatano, Versican/PG-M is essential for ventricular septal formation subsequent to cardiac atrioventricular cushion development. 2012, Pubmed
Hulander, Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice. 2003, Pubmed
Jalink, G protein-coupled receptors: the inside story. 2009, Pubmed
Kang, Molecular cloning and developmental expression of a hyaluronan and proteoglycan link protein gene, crtl1/hapln1, in zebrafish. 2009, Pubmed
Kang, Characterization of dermacan, a novel zebrafish lectican gene, expressed in dermal bones. 2004, Pubmed
Kelsh, Expression of zebrafish fkd6 in neural crest-derived glia. 2000, Pubmed
Kobayashi, Epithelial-mesenchymal transition as a possible mechanism of semicircular canal morphogenesis in chick inner ear. 2008, Pubmed
Koirala, Identification of novel glial genes by single-cell transcriptional profiling of Bergmann glial cells from mouse cerebellum. 2010, Pubmed
Kwakkenbos, Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells. 2004, Pubmed
Lang, Functional significance of channels and transporters expressed in the inner ear and kidney. 2007, Pubmed
Lang, Cell proliferation and cell death in the developing chick inner ear: spatial and temporal patterns. 2000, Pubmed
Li, Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling. 2010, Pubmed
Lin, Gbx2 is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling. 2005, Pubmed
Lister, nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate. 1999, Pubmed
Martin, Descriptive and experimental analysis of the epithelial remodellings that control semicircular canal formation in the developing mouse inner ear. 1993, Pubmed
Megerian, A mouse model with postnatal endolymphatic hydrops and hearing loss. 2008, Pubmed
Merlo, The Dlx5 homeobox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP4-mediated pathway. 2002, Pubmed , Xenbase
Michelmore, Identification of markers linked to disease-resistance genes by bulked segregant analysis: a rapid method to detect markers in specific genomic regions by using segregating populations. 1991, Pubmed
Milhaud, Chloride secretion by semicircular canal duct epithelium is stimulated via beta 2-adrenergic receptors. 2002, Pubmed
Monk, A G protein-coupled receptor is essential for Schwann cells to initiate myelination. 2009, Pubmed
Monk, Gpr126 is essential for peripheral nerve development and myelination in mammals. 2011, Pubmed
Moriguchi, DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites. 2004, Pubmed
Morsli, Otx1 and Otx2 activities are required for the normal development of the mouse inner ear. 1999, Pubmed
Neuhauss, Mutations affecting craniofacial development in zebrafish. 1997, Pubmed
Noda, Restriction of Wnt signaling in the dorsal otocyst determines semicircular canal formation in the mouse embryo. 2012, Pubmed
Odenthal, fork head domain genes in zebrafish. 1998, Pubmed
Oka, The fifth class of Galpha proteins. 2009, Pubmed
Patra, Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. 2013, Pubmed
Pfeffer, Characterization of three novel members of the zebrafish Pax2/5/8 family: dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function. 1998, Pubmed
Piotrowski, The zebrafish van gogh mutation disrupts tbx1, which is involved in the DiGeorge deletion syndrome in humans. 2003, Pubmed
Pittlik, Expression of zebrafish aldh1a3 (raldh3) and absence of aldh1a1 in teleosts. 2008, Pubmed
Pogoda, A genetic screen identifies genes essential for development of myelinated axons in zebrafish. 2006, Pubmed
Pondugula, cAMP-stimulated Cl- secretion is increased by glucocorticoids and inhibited by bumetanide in semicircular canal duct epithelium. 2013, Pubmed
Pradervand, A comprehensive analysis of gene expression profiles in distal parts of the mouse renal tubule. 2010, Pubmed
Rakowiecki, Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. 2013, Pubmed
Reifers, Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis. 1998, Pubmed
Ricciardelli, The biological role and regulation of versican levels in cancer. 2009, Pubmed
Sahly, The zebrafish eya1 gene and its expression pattern during embryogenesis. 1999, Pubmed
Salminen, Netrin 1 is required for semicircular canal formation in the mouse inner ear. 2000, Pubmed
Schultz, A new enzymatic assay for guanosine 3':5'-cyclic monophosphate and its application to the ductus deferens of the rat. 1973, Pubmed
Seamon, Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein. 1981, Pubmed
Shawi, Identification of a BMP7 homolog in zebrafish expressed in developing organ systems. 2008, Pubmed , Xenbase
Solomon, Zebrafish foxi1 mediates otic placode formation and jaw development. 2003, Pubmed
Stacey, The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. 2003, Pubmed
Sunose, cAMP increases K+ secretion via activation of apical IsK/KvLQT1 channels in strial marginal cells. 1998, Pubmed
Sunose, cAMP increases apical IsK channel current and K+ secretion in vestibular dark cells. 1997, Pubmed , Xenbase
Van Laer, Mice lacking Dfna5 show a diverging number of cochlear fourth row outer hair cells. 2005, Pubmed
Waller-Evans, The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. 2010, Pubmed
Wang, Hmx2 homeobox gene control of murine vestibular morphogenesis. 2001, Pubmed
Wang, Hmx2 and Hmx3 homeobox genes direct development of the murine inner ear and hypothalamus and can be functionally replaced by Drosophila Hmx. 2004, Pubmed
Waterman, Epithelial fusion during early semicircular canal formation in the embryonic zebrafish, Brachydanio rerio. 1984, Pubmed
Whitfield, Mutations affecting development of the zebrafish inner ear and lateral line. 1997, Pubmed
Wight, Versican: a versatile extracellular matrix proteoglycan in cell biology. 2002, Pubmed
Yona, Adhesion-GPCRs: emerging roles for novel receptors. 2008, Pubmed
Abraira, Cross-repressive interactions between Lrig3 and netrin 1 shape the architecture of the inner ear. 2008, Pubmed
Acampora, Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. 1999, Pubmed
Araç, A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. 2012, Pubmed
Asai, Mutation of the atrophin2 gene in the zebrafish disrupts signaling by fibroblast growth factor during development of the inner ear. 2006, Pubmed
Babb-Clendenon, Cadherin-2 participates in the morphogenesis of the zebrafish inner ear. 2006, Pubmed
Bahary, The Zon laboratory guide to positional cloning in zebrafish. 2004, Pubmed
Bakkers, Has2 is required upstream of Rac1 to govern dorsal migration of lateral cells during zebrafish gastrulation. 2004, Pubmed , Xenbase
Bissonnette, Standard atlas of the gross anatomy of the developing inner ear of the chicken. 1996, Pubmed
Bjarnadóttir, The adhesion GPCRs: a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues. 2007, Pubmed
Bjarnadóttir, The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. 2004, Pubmed
Blasiole, Neuronal calcium sensor-1 gene ncs-1a is essential for semicircular canal formation in zebrafish inner ear. 2005, Pubmed
Blasiole, Separate Na,K-ATPase genes are required for otolith formation and semicircular canal development in zebrafish. 2006, Pubmed
Bok, Patterning and morphogenesis of the vertebrate inner ear. 2007, Pubmed
Brösamle, Characterization of myelination in the developing zebrafish. 2002, Pubmed
Busch-Nentwich, The deafness gene dfna5 is crucial for ugdh expression and HA production in the developing ear in zebrafish. 2004, Pubmed
Cantos, Patterning of the mammalian cochlea. 2000, Pubmed
Carney, Genetic analysis of fin development in zebrafish identifies furin and hemicentin1 as potential novel fraser syndrome disease genes. 2010, Pubmed
Cecconi, Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth. 2004, Pubmed
Chang, Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements. 2008, Pubmed
Chang, The development of semicircular canals in the inner ear: role of FGFs in sensory cristae. 2004, Pubmed
Chen, Functions of hyaluronan in wound repair. 1999, Pubmed
Chiang, Two sox9 genes on duplicated zebrafish chromosomes: expression of similar transcription activators in distinct sites. 2001, Pubmed
Cruz, Plasma membrane calcium ATPase required for semicircular canal formation and otolith growth in the zebrafish inner ear. 2009, Pubmed
Deng, Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear. 2010, Pubmed
Dutton, A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. 2009, Pubmed
Dutton, Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. 2001, Pubmed
Elks, A role for soluble cAMP phosphodiesterases in differentiation of 3T3-L1 adipocytes. 1985, Pubmed
Enomoto, Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. 2010, Pubmed
Everett, Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. 2001, Pubmed
Fekete, Involvement of programmed cell death in morphogenesis of the vertebrate inner ear. 1997, Pubmed
Fritzsch, Otx1 null mutant mice show partial segregation of sensory epithelia comparable to lamprey ears. 2001, Pubmed
Glenn, Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin. 2013, Pubmed , Xenbase
Haddon, Hyaluronan as a propellant for epithelial movement: the development of semicircular canals in the inner ear of Xenopus. 1992, Pubmed , Xenbase
Haddon, Early ear development in the embryo of the zebrafish, Danio rerio. 1996, Pubmed
Hadrys, Nkx5-1 controls semicircular canal formation in the mouse inner ear. 1998, Pubmed
Hammerschmidt, Genetic analysis of dorsoventral pattern formation in the zebrafish: requirement of a BMP-like ventralizing activity and its dorsal repressor. 1996, Pubmed
Hammond, Repression of Hedgehog signalling is required for the acquisition of dorsolateral cell fates in the zebrafish otic vesicle. 2010, Pubmed
Hammond, The developing lamprey ear closely resembles the zebrafish otic vesicle: otx1 expression can account for all major patterning differences. 2006, Pubmed
Han, Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28. 2011, Pubmed
Hatano, Versican/PG-M is essential for ventricular septal formation subsequent to cardiac atrioventricular cushion development. 2012, Pubmed
Hulander, Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice. 2003, Pubmed
Jalink, G protein-coupled receptors: the inside story. 2009, Pubmed
Kang, Molecular cloning and developmental expression of a hyaluronan and proteoglycan link protein gene, crtl1/hapln1, in zebrafish. 2009, Pubmed
Kang, Characterization of dermacan, a novel zebrafish lectican gene, expressed in dermal bones. 2004, Pubmed
Kelsh, Expression of zebrafish fkd6 in neural crest-derived glia. 2000, Pubmed
Kobayashi, Epithelial-mesenchymal transition as a possible mechanism of semicircular canal morphogenesis in chick inner ear. 2008, Pubmed
Koirala, Identification of novel glial genes by single-cell transcriptional profiling of Bergmann glial cells from mouse cerebellum. 2010, Pubmed
Kwakkenbos, Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells. 2004, Pubmed
Lang, Functional significance of channels and transporters expressed in the inner ear and kidney. 2007, Pubmed
Lang, Cell proliferation and cell death in the developing chick inner ear: spatial and temporal patterns. 2000, Pubmed
Li, Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling. 2010, Pubmed
Lin, Gbx2 is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling. 2005, Pubmed
Lister, nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate. 1999, Pubmed
Martin, Descriptive and experimental analysis of the epithelial remodellings that control semicircular canal formation in the developing mouse inner ear. 1993, Pubmed
Megerian, A mouse model with postnatal endolymphatic hydrops and hearing loss. 2008, Pubmed
Merlo, The Dlx5 homeobox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP4-mediated pathway. 2002, Pubmed , Xenbase
Michelmore, Identification of markers linked to disease-resistance genes by bulked segregant analysis: a rapid method to detect markers in specific genomic regions by using segregating populations. 1991, Pubmed
Milhaud, Chloride secretion by semicircular canal duct epithelium is stimulated via beta 2-adrenergic receptors. 2002, Pubmed
Monk, A G protein-coupled receptor is essential for Schwann cells to initiate myelination. 2009, Pubmed
Monk, Gpr126 is essential for peripheral nerve development and myelination in mammals. 2011, Pubmed
Moriguchi, DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites. 2004, Pubmed
Morsli, Otx1 and Otx2 activities are required for the normal development of the mouse inner ear. 1999, Pubmed
Neuhauss, Mutations affecting craniofacial development in zebrafish. 1997, Pubmed
Noda, Restriction of Wnt signaling in the dorsal otocyst determines semicircular canal formation in the mouse embryo. 2012, Pubmed
Odenthal, fork head domain genes in zebrafish. 1998, Pubmed
Oka, The fifth class of Galpha proteins. 2009, Pubmed
Patra, Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. 2013, Pubmed
Pfeffer, Characterization of three novel members of the zebrafish Pax2/5/8 family: dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function. 1998, Pubmed
Piotrowski, The zebrafish van gogh mutation disrupts tbx1, which is involved in the DiGeorge deletion syndrome in humans. 2003, Pubmed
Pittlik, Expression of zebrafish aldh1a3 (raldh3) and absence of aldh1a1 in teleosts. 2008, Pubmed
Pogoda, A genetic screen identifies genes essential for development of myelinated axons in zebrafish. 2006, Pubmed
Pondugula, cAMP-stimulated Cl- secretion is increased by glucocorticoids and inhibited by bumetanide in semicircular canal duct epithelium. 2013, Pubmed
Pradervand, A comprehensive analysis of gene expression profiles in distal parts of the mouse renal tubule. 2010, Pubmed
Rakowiecki, Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. 2013, Pubmed
Reifers, Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis. 1998, Pubmed
Ricciardelli, The biological role and regulation of versican levels in cancer. 2009, Pubmed
Sahly, The zebrafish eya1 gene and its expression pattern during embryogenesis. 1999, Pubmed
Salminen, Netrin 1 is required for semicircular canal formation in the mouse inner ear. 2000, Pubmed
Schultz, A new enzymatic assay for guanosine 3':5'-cyclic monophosphate and its application to the ductus deferens of the rat. 1973, Pubmed
Seamon, Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein. 1981, Pubmed
Shawi, Identification of a BMP7 homolog in zebrafish expressed in developing organ systems. 2008, Pubmed , Xenbase
Solomon, Zebrafish foxi1 mediates otic placode formation and jaw development. 2003, Pubmed
Stacey, The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. 2003, Pubmed
Sunose, cAMP increases K+ secretion via activation of apical IsK/KvLQT1 channels in strial marginal cells. 1998, Pubmed
Sunose, cAMP increases apical IsK channel current and K+ secretion in vestibular dark cells. 1997, Pubmed , Xenbase
Van Laer, Mice lacking Dfna5 show a diverging number of cochlear fourth row outer hair cells. 2005, Pubmed
Waller-Evans, The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. 2010, Pubmed
Wang, Hmx2 homeobox gene control of murine vestibular morphogenesis. 2001, Pubmed
Wang, Hmx2 and Hmx3 homeobox genes direct development of the murine inner ear and hypothalamus and can be functionally replaced by Drosophila Hmx. 2004, Pubmed
Waterman, Epithelial fusion during early semicircular canal formation in the embryonic zebrafish, Brachydanio rerio. 1984, Pubmed
Whitfield, Mutations affecting development of the zebrafish inner ear and lateral line. 1997, Pubmed
Wight, Versican: a versatile extracellular matrix proteoglycan in cell biology. 2002, Pubmed
Yona, Adhesion-GPCRs: emerging roles for novel receptors. 2008, Pubmed