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
References [+] :
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Chang, The development of semicircular canals in the inner ear: role of FGFs in sensory cristae. 2004, Pubmed
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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
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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