3. Formation of otoconia and otoliths requires a stepwise process Normal generation of otoconia requires the orchestration of complex temporal and spatial developmental and biochemical events. In the mouse, the first seeding of CaCO 3 crystals takes place at E14 and otoconia with defined forms can first be observed at E15–16, but genetic evidence suggests that the processes necessary for normal otoconial development begin much earlier. Normal otoconial formation requires (1) the correct induction and formation of the otocyst; (2) specification and differentiation of the sensory maculae and sensory and supporting cells; (3) establishing the correct ionic environment that allows for normal export and processing of matrix proteins and ions; (4) production and export of the otoconial matrix proteins and gelatinous membrane; (5) assembly of a protein core from free-floating matrix proteins; and (6) locally increasing Ca 2+ and carbonate (
) concentrations to initiate crystal formation on the proteinaceous core. The above elements must occur in a specific order and within specific time points to develop correctly formed otoconia or otoliths. Calcification, once initiated, must occur only above the utricular and saccular sensory maculae to prevent general mineralization in the ear which could severely impair balance and auditory function. The temporal specificity of otoconial development is determined by a combination of localized production of key elements and most likely by removal of excess otoconial proteins through the endolymphatic sac ( Ignatova et al., 2004). In addition, the expression of inhibitors of calcification, which prevents mineralization of the rest of the endolymph, is probably complementary to the expression of pro-calcifying proteins, further specifying the time of otoconial/otolith initiation to a tight window during development and restricting locations of mineralization. Support for a critical period of otoconial development comes from dietary studies (Zn 2+ rescue of lethal milk mice; Erway and Grider, 1984) and from studies in the fish in which otoconial formation is delayed using laser ablation or gene dosage ( Hughes et al., 2004; Riley et al., 1997). Spatial specificity is most likely conferred by specific sets of integrins which localize otoconial matrix proteins to the sensory maculae and by the interactions of mineralizing matrix vesicles with specific extracellular matrix proteins in the developing gelatinous membrane. Disruptions of any of these elements can lead to lack of formation of the CaCO 3 biominerals (otoconial/otolith agenesis) or can lead to the formation of inorganic crystals which lack organized matrix. 3.1. Form a normal otocyst Patterning of the developing otocyst requires interaction of the developing hindbrain with the overlying neurectoderm. Disruptions in inner ear patterning through alterations in the development of the hindbrain rhombomeres have been well documented through the study of naturally occurring mutants and engineered knockout and transgenic mice. In several of these animals, otoconial defects have been described, or can be assumed, based on the severity of the developmental anomalies in inner ear formation. Targeted deletions of Otx1, one of the earliest expressed transcription factors in the inner ear, lead to impaired otic development, characterized by a continuous utricular and saccular epithelium. Otx1−/− mice do not develop otoconia despite formation of a small, relatively normal sensory epithelium ( Morsli et al., 1999). Similarly, Tbx1 mutants do not form the normal structures of the inner ear, and the single macula formed in these mutant ears does not develop otoconia ( Vitelli et al., 2003). The zebrafish valentino (val) mutant ectopically expresses fgf3 in the hindbrain causing alterations in otocyst formation. Otoliths in val mutants are poorly adherent and fail to associate with the sensory maculae ( Kwak et al., 2002). Acerebellar (ace) zebrafish mutants, which inactivate the fgf8 gene, typically have a small otocyst, abnormal semicircular canals, and only one otolith ( Leger and Brand, 2002). The foxi1 mutant hearsay often forms a single otic vesicle with one otolith ( Solomon et al., 2003). Foxi1 is upstream of several transcription factors required for normal otic morphogenesis and regulates the expression of the anion transporter pendrin which is important in endolymph ionic regulation (discussed below) ( Table 1). 3.2. Form normal macular compartments (utricle/saccule sensory regions) and the nonsensory epithelium The formation of the sensory macula requires the formation of boundaries separating presumptive neural tissue from surrounding nonsensory support structures. At these boundaries, nonsensory transitional cells will form, which have been shown to have an important role in the secretion of the extra-cellular matrix of the otoconial/otolithic membrane and may have a role in the maintenance of otoconia later in life ( Murayama et al., 2000; Yamane et al., 1984). While the definition of the sensory region is required for otoconial initiation, the formation of mature sensory hair cells or mature supporting cells does not appear to be necessary. Mouse mutants in Atoh-1/Math1 do not develop sensory hair cells, but have a normal appearing otoconial membrane ( Bermingham et al., 1999). Similarly, mature supporting cells are not required for normal otolith formation as the zebrafish mindbomb mutant, which generates only sensory hair cells due to a lack of lateral inhibition, can initiate otolith formation ( Haddon et al., 1999). This suggests that initiation of otoconial development is determined by the interaction of Oc90 and activities of the early macular cells before hair cells and supporting cells acquire lineage specific properties. Formation of the precursor cells from which both vestibular hair and supporting cells are derived is both necessary and sufficient (in the presence of Oc90) for otoconial initiation and development, as it has been shown that ectopic vestibular type hair and supporting cells induced by Wnt overexpression in the cochlea can produce small regions of relatively normal looking otoconial membrane and otoconia ( Stevens et al., 2003). Alteration in the size of the sensory maculae causes an associated change in the size of the developing otolith. The dog eared zebrafish mutants have truncation mutations within the transcription factor Eya1 (a homologue of the Drosophila eyes absent 1) and have small utricular and saccular maculae due to increased cell death during early stages of inner ear development. These animals have significantly undersized otoliths, which may correlate with reduced CaCO 3 and minor otoconin production by the degenerating maculae ( Kozlowski et al., 2005; Whitfield et al., 1996). Similarly, colourless (cls) zebrafish mutants have tiny otoliths that correlate well with the diminished macular size of the utricle and saccule. The cls mutation leads to alteration in the activity of Sox10, a transcription factor required for neural crest differentiation. However, Sox10 activity in the otocyst is independent of its role in neural crest identity ( Dutton et al., 2001). Sox10 is believed to play a role in specifying macular fate ( Dutton et al., 2001), and its expression is reduced in cls otocyst as is the expression of otx1 and mshC, markers of presumptive macular components ( Whitfield et al., 1996). After the maculae are specified, changes in the relative density of hair cells and supporting cells can also lead to alterations in otolith formation. Otolith formation is delayed until 30 hpf in the zebrafish mutant in deltaA, a component of the Notch lateral inhibition system. DeltaA-deficient fish have malformed otoliths that appear elongated across the macula most likely due to an increase in the number of tether cells, which anchor otolith core proteins to the macula ( Riley et al., 1999). Similarly, mindbomb mutants, which also form excess hair cells without supporting cells, fail to enlarge their otoliths by 60 hpf ( Haddon et al., 1998). The otoliths in these mutants are poorly adherent and have increased mineralization ( Haddon et al., 1999). 3.3. Establish the ionic environment The endolymph of the inner ear represents a unique extracellular ionic milieu. While measurements of ionic composition have not been done in the embryonic/developing ear, young adult studies suggest that endolymph has concentrations of Ca 2+ (~20–100 μM) and sodium (<1 mM), considerably lower than that in the serum ( Salt et al., 1989). This unique extracellular fluid is maintained by cells throughout the inner ear including the vestibular dark cells of the thin nonsensory epithelium of the utricle ( Fermin et al., 1990; Hsu, 1991; Ichimiya et al., 1994), the stria vascularis ( Kambayashi et al., 1982; Kusakari et al., 1978), the fibrocytes of the spiral ligament ( Spicer and Schulte, 1991), and the endolymphatic sac and endolymphatic duct ( Salt et al., 1989; Thalmann and Thalmann, 1999). Specialized tight junctions and interactions with a complex basement membrane are required to maintain the activities of these compartments. Disruptions in any of these structures could lead to significant alterations in endolymph ionic content and pH and thus alteration in otoconial formation and maintenance. The dancer mouse has an abnormally high concentration of PO 4 in otoconia ( Anniko et al., 1988), suggesting a defect in the ionic environment and crystal formation. Dancer mice have subtle abnormalities in inner ear structure that suggests alterations in the development the endolymphatic sac and duct and the spiral ligament ( Anniko et al., 1988). This phenotype is the result of an insertion mutation of a portion of the p23 gene into the Tbx10 locus, leading to ectopic and overexpression of the Tbx10 transcript in a near ubiquitous pattern, as opposed to its normal highly restricted expression in rhombomere 4 ( Bush et al., 2004). Alterations in ionic content in this case are due to abnormalities of the organization of the inner ear compartments required for endolymph regulation. Specific loss of individual ion-regulators has also been shown to lead to abnormalities in otoconial formation. The Plasma Membrane Calcium ATPase 2 (PMCA2) has been implicated in the maintenance of endolymph Ca 2+ levels. Animals deficient in PMCA2 show an intact macular epithelium and gelatinous membrane but lack otoconia ( Kozel et al., 1998). PMCA2 has been proposed as the primary Ca 2+ pump for maintenance of endolymph Ca 2+ levels, and other Ca 2+ pump mutants have not been shown to affect inner ear development ( Shull et al., 2003). It may be that the role of PMCA2 in general maintenance of endolymph Ca 2+ is required for normal otoconial development; alternatively, PMCA2 may have a more direct role in locally increasing Ca 2+ during otoconia formation. Pendrin (Pds) is an anion transporter of the solute carrier 26 family. Loss of Pendrin activity leads to Pendred syndrome, an autosomal recessive syndrome characterized by deafness and goiter. Pendrin specifically transports chloride and iodide and is thought to be important for endolymphatic fluid resorption in the inner ear ( Everett et al., 1999). Pds−/− mice lack otoconia or develop giant otoconia ( Everett et al., 2001), but also have significant defects in the remainder of the ear, including stereociliary degeneration. Foxi1, a forkhead transcription factor, regulates expression of Pendrin in the developing inner ear. Loss of function of Foxi1 also leads to Pendred syndrome, with expansion of the endolymph compartment leading to auditory and vestibular dysfunction ( Hulander et al., 2003). Claudinj (cldnj) is a component of tight junctions in the inner ear. Zebrafish cldnj mutants develop normal sensory structures within the inner ear, but their otoliths are severely reduced in size and unincorporated otolith core material can be seen throughout the early otic vesicle ( Hardison et al., 2005). Claudinj is expressed in the nonsensory epithelium opposite the developing sensory maculae; Hardison et al. (2005) propose that loss of this protein causes a deficiency in some barrier function of the dorsolateral wall of the otocyst for specific ions required in the endolymph for otolith core matrix aggregation ( Hardison et al., 2005). 3.4. Make and export the matrix proteins correctly As with any extracellular matrix, normal protein production, posttranslational modification, packaging, and movement into the extracellular space are required for otoconial and otolith formation. Oc90 accounts for 90% of the total protein of the otoconial core and is expressed by the nonsensory epithelium of the inner ear ( Verpy et al., 1999; Wang et al., 1998). Knockout mice for Oc90 initially develop giant otoconia, suggesting that Oc90 is essential for normal otoconial formation (Y. Lundberg, personal communication). The Oc90 protein within otoconia is highly glycosylated, suggesting that mutations or disruption of the activity of glycosylating enzymes would lead to abnormalities in otoconial formation. Indeed, depletion of the divalent cation manganese (Mn 2+), an important cofactor for glycosylating enzymes, leads to a significant decrease in the synthesis of sulfated glycoproteins/proteoglycans and agenesis of otoconia in mammals and birds ( Erway et al., 1986). Two of the “minor” otoconins have been identified as the ubiquitous calcium binding proteins osteopontin ( Sakagami, 2000; Takemura et al., 1994) and calbindin D28K (in chick and lizard) ( Balsamo et al., 2000; Piscopo et al., 2003), which are believed to be produced in the developing sensory macula. Oc90 has 2 EF hands and has been shown to bind Ca 2+ (I. Thalmann, unpublished data); osteopontin and calbindin have similar calcium binding motifs. Several other minor constituents of the mammalian otoconial core were identified using microscale protein preparatory techniques and tandem mass spectroscopy and include fetuin, a proposed inhibitor of calcium phosphate-based calcification; myosin regulatory light polypeptide 9, which contains 2 EF-hand domains and binds calcium; osteopontin, a sialoprotein, known to be a component of the matrix of bone and other calcified tissue; SC-1 (also known as “hevin”), a member of the SPARC family of matricellular proteins, which mediate interactions between cells and their extracellular matrices; and laminin α3, a component of basal lamina involved in attaching cells to the extracellular matrix via interactions with integrins ( Thalmann et al., in press). In the teleost fish, three major matrix proteins have been described: starmaker, otolith matrix protein, and otolin. Starmaker is homologous to dental sialophosphoprotein (DSPP) in mammals, which is required for the normal mineralization of teeth ( Sollner et al., 2003). DSPP mutations have been shown to result in Dentinogenesis Imperfecta ( Sreenath et al., 2003). Morpholino-mediated knockdown of starmaker leads to a delay in otolith formation as well as loss of the core particles and other proteinaceous components of the developing crystal. In animals injected with very high doses of starmaker morpholino, otoliths consist of inorganic CaCO 3 and have an altered crystal structure ( Sollner et al., 2003), most likely due to an inability to coordinate and organize the CaCO 3 into the complex biomineral of the normal otolith. Otolith matrix protein (omp) is the primary matrix protein of the aragonitic fish otolith ( Murayama et al., 2000). Omp morphant fish initiate normal otolith formation, but have significantly reduced rates of otolith growth, suggesting that omp is not required for otolith initiation but is required for the daily growth increments ( Murayama et al., 2002). Otolin, first identified in trout ( Murayama et al., 2002; Takagi and Takahashi, 1999), is expressed by the transitional cells of the developing sacculus and has short collagen like repeats similar to collagen X ( Murayama et al., 2002). Otolin is similar to the fish saccular collagen proposed to have a role in the calcification process of the aragonitic otolith ( Davis et al., 1995, 1997); this has been supported by the phenotype of otolin morphants. Morphant otoliths lose adherence to the sensory maculae (but not to hair cell kinocilia) and fuse by 72 hpf. Interestingly, otolin morphant otoliths spontaneously decalcify and swell during experimental procedures, suggesting that otolin is required to fully organize the inorganic and organic components required to generate mineralized otoliths in addition to a function as part of the gelatinous membrane anchoring the otolith close to the sensory maculae ( Murayama et al., 2005). The gelatinous membrane and the underlying subcupular meshwork are made up of many proteins and extracellular matrix molecules. The fish otolithic membrane appears much simpler than the mammalian otoconial membrane ( Fig. 1C), with a thick fibrillar network that connects each hair cell stereociliary bundle to the otolith, but is predicted to have similar biochemical complexity ( Khan and Drescher, 1990). Organic substances, including acidic proteins, glycosaminoglycans (GAGs), and proteoglycans, are essential to regulate crystal growth ( Addadi et al., 1989; Khan, 1997) and have been identified in both otoliths ( Borelli et al., 2003b) and otoconia ( Tachibana and Morioka, 1992). Sulfated GAGs may play a crucial role in locally increasing Ca 2+ concentration at the site of biomineralization, as is discussed in more detail below. Proteins of the gelatinous membrane that have been identified include α-tectorin, β-tectorin, otolin (in the fish and probably other vertebrates as well), and otogelin. Knockout mice for α-tectorin had significant abnormalities of the extracellular matrices of the inner ear, including decreased thickness of the gelatinous membrane in the utricle and saccule, a complete lack of utricular otoconia and abnormal or giant otoconia in the saccule ( Cohen-Salmon et al., 1997; Legan et al., 2000). This suggests that the integrity of the structure of the gelatinous membrane and subcupular meshwork is required for normal otoconial development. 3.5. Assemble and attach matrix proteins in the right place in the inner ear Assembly of the otoconial complex in the aqueous endolymphatic space and its maintenance above the sensory maculae require a variety of adhesion molecules. In particular, at least two adhesion molecule complexes appear to be required to first localize the major core protein Oc90 specifically to the otoconial membrane during development and to then maintain adherence of calcified mature otoconia to the gelatinous membrane. The integrins or other molecular recognition and adhesion molecules required for otoconial formation have not yet been identified, though Otogelin and Otoancorin have been shown to be required to maintain adhesion of the mature otoconial membrane to the sensory maculae. The Otogelin (Otog) mutant twister and targeted deletion of Otogelin result in deafness and considerable balance deficits. Otog null mice initially form normal otoconia, but shortly after birth the gelatinous membrane and otoconia detach from both the utricular and saccular maculae, indicating that Otogelin is essential for anchoring the otoconial complex to the sensory epithelium ( Cohen-Salmon et al., 1997; Simmler et al., 2000a, b). Otoancorin is expressed by supporting cells and is localized to the point of interaction between the support cells and the acellular otoconial membrane ( Zwaenepoel et al., 2002). Several zebrafish mutants have been described with aberrant otolith attachment that support the hypothesis that two independent adhesion complexes are required for otolith formation and maintenance. The monolith mutant has only one otolith, found on either of the two early sensory epithelia or at an ectopic location in the inner ear. Without the monolith gene signal from supporting cells, the early tether cells were not capable of binding pre-otolith core particles and attaching them to developing sensory maculae ( Riley and Grunwald, 1996; Riley and Moorman, 2000). In these animals, a single otolith is formed from the free-floating otolith core particles and attaches later in development to either of the sensory epithelia, depending on orientation of the fish ( Riley and Moorman, 2000). Similarly, the einstein and menhir mutants have only one aberrant otolith despite normal macular formation, which suggests that a group of genes is required to attach otolith core particles to the tether cells ( Whitfield et al., 1996). The GP96 morphant fish mimic these adherence mutants in that they do not attach otolith core particles to the tether cells. GP96 is a heat shock protein and molecular chaperone which has been described in mouse cells to be involved in the correct processing of Toll-like receptors and integrins ( Sumanas et al., 2003). The rolling stones mutant cannot attach otoliths later in life, though they initially attach the core particles to tether cells and initiate normal otolith formation. After mineralization, rolling stones otoliths are free to move about the inner ear. It is only when the stones shift onto a sensory macula that the developing fish can orient and swim normally ( Whitfield et al., 1996). Cloning and further characterization of these and other zebrafish otolith adherence mutants may reveal important aspects of otoconial and otolith adhesion that may help to identify factors involved in the etiology of Benign Positional Vertigo. 3.6. Locally increase calcium and carbonate concentrations to initiate otolith/otoconial growth Once adherence of early otoconial and otolith matrix particles to the maculae occurs, deposition of CaCO 3 is rapid. The essential requirement to form CaCO 3 is the availability of Ca 2+ and
ions. The latter depend on the availability of carbonic anhydrase, which is abundant in the inner ear ( Lim et al., 1983; Shiao et al., 2005). This has been supported both by lack of otoconial formation in rodent and chick embryos treated with carbonic anhydrase inhibitors ( Kido et al., 1991) as well as dietary studies which have shown that severe deficiency of Zn 2+, an essential cofactor for carbonic anhydrase activity, leads to otoconial agenesis ( Erway and Grider, 1984; Erway et al., 1986). Little is currently known about the source of Ca 2+ in otoconial formation. It is believed that PMCA2 has a significant role in establishing the Ca 2+ concentration within the endolymph as discussed above, but a role specifically in otoconial formation has not been identified for this protein. Several mouse mutants have been characterized that appear to have primary defects in otoconial mineralization. Head tilt (het) and head slant (hslt) mutants have complete lack of otoconial mineralization despite the presence of Oc90 in the developing inner ear. The het phenotype results from a recessive mutation within the gene encoding NADPH-Oxidase 3 (NOX3), a reactive oxygen species generating oxidase specific to the inner ear ( Banfi et al., 2004; Paffenholz et al., 2004). Hslt mice, with a similar lack of otoconia, carry a mutation in an accessory protein for NOX3 and NOXO1 ( Kiss et al., 2006). NOX3 and NOXA1 are localized to the sensory maculae and het and hslt mice are proposed to have significant alterations in the formation of reactive oxygen species (ROS). The role of ROS in otoconial formation has not yet been elucidated, though much work in other model systems has shown that ROS generation is coupled to alterations in mitochondrial and endoplasmic reticulum Ca 2+ regulation ( Ermak and Davies, 2002), which may be required for concentrating the Ca 2+ used for otoconial mineralization (discussed below). Similar to the phenotypes seen in het and hslt mice, the tilted (tlt), mergulhador (mlh), and inner ear defect (ied) mice carry mutations in the novel multi-transmembrane domain protein, Otopetrin 1 (Otop1), resulting in nonsyndromic otoconial agenesis and a severe balance disorder in mice ( Besson et al., 2005; Hurle et al., 2003; Ornitz et al., 1998). The zebrafish otop1 orthologue is a highly conserved gene that is essential for otolith initiation as seen in both morphant otop1 fish and in the backstroke mutant ( Hughes et al., 2004; Sollner et al., 2004). Despite lack of otoliths in early development, otop1 morphant fish partially recover otolith formation after 2 days, in a timeframe consistent with dilution of the morpholino and reexpression of otop1, indicating that Otop1 has an essential and conserved role in the timing of formation and the size and shape of the developing otolith. In mouse, Otop1 immunoreactivity localizes to the otoconial membrane in the utricular and saccular maculae; this suggests that Otop1 is localized to extracellular vesicles, called globular substance, that have been suggested to be the site of initiation of otoconial mineralization ( Erway et al., 1986; Preston et al., 1975; Ross, 1979). Globular substance vesicles are proposed to bud from the supporting cells (or the precursor cells) of the sensory macula ( Suzuki et al., 1995, 1997b). This hypothesis is supported by electron microscopic data ( Anniko et al., 1987; Kawamata and Igarashi, 1993; Lim, 1973) that have shown cytoplasmic blebs at the surface of supporting cells or within the otoconial membrane, similar to those seen in chondrocytes before the release of matrix vesicles during bone mineralization. |
References - Addadi, L; Berman, A; Oldak, JM; Weiner, S. Structural and stereochemical relations between acidic macromolecules of organic matrices and crystals. Connect Tissue Res. 1989;21:127–134. discussion 135. [PubMed]
- Alagramam, KN; Murcia, CL; Kwon, HY; Pawlowski, KS; Wright, CG; Woychik, RP. The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nat Genet. 2001;27:99–102. [PubMed]
- Alagramam, KN; Stahl, JS; Jones, SM; Pawlowski, KS; Wright, CG. Characterization of vestibular dysfunction in the mouse model for Usher syndrome 1F. J Assoc Res Otolaryngol. 2005;6:106–118. [PubMed]
- Anderson, HC. Matrix vesicles and calcification. Curr Rheumatol Rep. 2003;5:222–226. [PubMed]
- Anniko, M. Development of otoconia. Am J Oto-Laryngol. 1980;1:400–410.
- Anniko, M; Wikstrom, SO; Wroblewski, R. X-ray microanalytic studies on developing otoconia. Acta Oto-Laryngol. 1987;104:285–289.
- Anniko, M; Wenngren, BI; Wroblewski, R. Aberrant elemental composition of otoconia in the dancer mouse mutant with a semidominant gene causing a morphogenetic type of inner ear defect. Acta Oto-Laryngol. 1988;106:208–212.
- Bachra, BN; Trautz, ON; Simon, SL. Precipitation of calcium carbonates and phosphates: 1. Spontaneous precipitation of calcium carbonates and phosphates under physiological conditions. Arch Biochem Biophys. 1963;103:124–138. [PubMed]
- Balkema, GW; Mangini, NJ; Pinto, LH. Discrete visual defects in pearl mutant mice. Science. 1983;219:1085–1087. [PubMed]
- Ballarino, J; Howland, HC. Otoconial morphology of the developing chick. Anat Rec. 1982;204:83–87. [PubMed]
- Balsamo, G; Avallone, B; Del Genio, F; Trapani, S; Marmo, F. Calcification processes in the chick otoconia and calcium binding proteins: patterns of tetracycline incorporation and calbindin-D28K distribution. Hear Res. 2000;148:1–8. [PubMed]
- Banfi, B; Malgrange, B; Knisz, J; Steger, K; Dubois-Dauphin, M; Krause, KH. NOX3, a superoxide-generating NADPH oxidase of the inner ear. J Biol Chem. 2004;279:46065–46072. [PubMed]
- Bermingham, NA; Hassan, BA; Price, SD; Vollrath, MA; Ben-Arie, N; Eatock, RA; Bellen, HJ; Lysakowski, A; Zoghbi, HY. Math1: an essential gene for the generation of inner ear hair cells. Science. 1999;284:1837–1841. [PubMed]
- Besson, V; Nalesso, V; Herpin, A; Bizot, JC; Messaddeq, N; Romand, R; Puech, A; Blanquet, V; Herault, Y. Training and aging modulate the loss-of-balance phenotype observed in a new ENU-induced allele of Otopetrin1. Biol Cell. 2005;97:787–798. [PubMed]
- Borelli, G; Guibbolini, ME; Mayer-Gostan, N; Priouzeau, F; De Pontual, H; Allemand, D; Puverel, S; Tambutte, E; Payan, P. Daily variations of endolymph composition: relationship with the otolith calcification process in trout. J Exp Biol. 2003a;206:2685–2692. [PubMed]
- Borelli, G; Mayer-Gostan, N; Merle, PL; Pontual, H; Boeuf, G; Allemand, D; Payan, P. Composition of biomineral organic matrices with special emphasis on turbot (Psetta maxima) otolith and endolymph. Calcif Tissue Int. 2003b;72:717–725. [PubMed]
- Bush, JO; Lan, Y; Jiang, R. The cleft lip and palate defects in Dancer mutant mice result from gain of function of the Tbx10 gene. Proc Natl Acad Sci U S A. 2004;101:7022–7027. [PubMed]
- Casimiro, MC; Knollmann, BC; Ebert, SN; Vary, JC, Jr; Greene, AE; Franz, MR; Grinberg, A; Huang, SP; Pfeifer, K. Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange–Nielsen Syndrome. Proc Natl Acad Sci U S A. 2001;98:2526–2531. [PubMed]
- Ciciotte, SL; Gwynn, B; Moriyama, K; Huizing, M; Gahl, WA; Bonifacino, JS; Peters, LL. Cappuccino, a mouse model of Hermansky–Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1). Blood. 2003;101:4402–4407. [PubMed]
- Cohen-Salmon, M; El-Amraoui, A; Leibovici, M; Petit, C. Otogelin: a glycoprotein specific to the acellular membranes of the inner ear. Proc Natl Acad Sci U S A. 1997;94:14450–14455. [PubMed]
- Crenshaw, EB, III; Ryan, A; Dillon, SR; Kalla, K; Rosenfeld, MG. Wocko, a neurological mutant generated in a transgenic mouse pedigree. J Neurosci. 1991;11:1524–1530. [PubMed]
- Croushore, JA; Blasiole, B; Riddle, RC; Thisse, C; Thisse, B; Canfield, VA; Robertson, GP; Cheng, KC; Levenson, R. Ptena and ptenb genes play distinct roles in zebrafish embryogenesis. Dev Dyn. 2005;234:911–921. [PubMed]
- Das, M. Age determination and longevity in fishes. Gerontology. 1994;40:70–96. [PubMed]
- Davis, JG; Oberholtzer, JC; Burns, FR; Greene, MI. Molecular cloning and characterization of an inner ear-specific structural protein. Science. 1995;267:1031–1034. [PubMed]
- Davis, JG; Burns, FR; Navaratnam, D; Lee, AM; Ichimiya, S; Oberholtzer, JC; Greene, MI. Identification of a structural constituent and one possible site of postembryonic formation of a teleost otolithic membrane. Proc Natl Acad Sci U S A. 1997;94:707–712. [PubMed]
- Dutton, KA; Pauliny, A; Lopes, SS; Elworthy, S; Carney, TJ; Rauch, J; Geisler, R; Haffter, P; Kelsh, RN. Zebrafish colourless encodes sox10 and specifies non-ectomesenchymal neural crest fates. Development. 2001;128:4113–4125. [PubMed]
- Ermak, G; Davies, KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol. 2002;38:713–721. [PubMed]
- Erway, LC; Grider, A., Jr Zinc metabolism in lethal-milk mice. Otolith, lactation, and aging effects. J Hered. 1984;75:480–484. [PubMed]
- Erway, LC; Purichia, NA; Netzler, ER; D’Amore, MA; Esses, D; Levine, M. Genes, manganese, and zinc in formation of otoconia: labeling, recovery, and maternal effects. Scan Electron Microsc. 1986:1681–1694. [PubMed]
- Everett, LA; Glaser, B; Beck, JC; Idol, JR; Buchs, A; Heyman, M; Adawi, F; Hazani, E; Nassir, E; Baxevanis, AD; Sheffield, VC; Green, ED. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet. 1997;17:411–422. [PubMed]
- Everett, LA; Morsli, H; Wu, DK; Green, ED. Expression pattern of the mouse ortholog of the Pendred’s syndrome gene (Pds) suggests a key role for pendrin in the inner ear. Proc Natl Acad Sci U S A. 1999;96:9727–9732. [PubMed]
- Everett, LA; Belyantseva, IA; Noben-Trauth, K; Cantos, R; Chen, A; Thakkar, SI; Hoogstraten-Miller, SL; Kachar, B; Wu, DK; Green, ED. Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet. 2001;10:153–161. [PubMed]
- Falcon-Perez, JM; Starcevic, M; Gautam, R; Dell’Angelica, EC. BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules. J Biol Chem. 2002;277:28191–28199. [PubMed]
- Farber, SA; De Rose, RA; Olson, ES; Halpern, ME. The zebrafish annexin gene family. Genome Res. 2003;13:1082–1096. [PubMed]
- Feng, L; Seymour, AB; Jiang, S; To, A; Peden, AA; Novak, EK; Zhen, L; Rusiniak, ME; Eicher, EM; Robinson, MS; Gorin, MB; Swank, RT. The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky–Pudlak syndrome and night blindness. Hum Mol Genet. 1999;8:323–330. [PubMed]
- Fermin, CD; Igarashi, M. Development of otoconia in the embryonic chick (Gallus domesticus). Acta Anat (Basel). 1985;123:148–152. [PubMed]
- Fermin, CD; Lovett, AE; Igarashi, M; Dunner, K., Jr Immunohistochemistry and histochemistry of the inner ear gelatinous membranes and statoconia of the chick (Gallus domesticus). Acta Anat (Basel). 1990;138:75–83. [PubMed]
- Flagella, M; Clarke, LL; Miller, ML; Erway, LC; Giannella, RA; Andringa, A; Gawenis, LR; Kramer, J; Duffy, JJ; Doetschman, T; Lorenz, JN; Yamoah, EN; Cardell, EL; Shull, GE. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946–26955. [PubMed]
- Fujii, M; Harada, Y; Hirakawa, K; Takumida, M. Otoconia on the vestibular dark cells of the ampullar areas. Acta Oto-Laryngol. 1995;Suppl. 519:140–142.
- Gamp, AC; Tanaka, Y; Lullmann-Rauch, R; Wittke, D; D’Hooge, R; De Deyn, PP; Moser, T; Maier, H; Hartmann, D; Reiss, K; Illert, AL; von Figura, K; Saftig, P. LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum Mol Genet. 2003;12:631–646. [PubMed]
- Gwynn, B; Ciciotte, SL; Hunter, SJ; Washburn, LL; Smith, RS; Andersen, SG; Swank, RT; Dell’Angelica, EC; Bonifacino, JS; Eicher, EM; Peters, LL. Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky–Pudlak syndrome by an AP-3-independent mechanism. Blood. 2000;96:4227–4235. [PubMed]
- Haddon, C; Jiang, YJ; Smithers, L; Lewis, J. Delta–Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant. Development. 1998;125:4637–4644. [PubMed]
- Haddon, C; Mowbray, C; Whitfield, T; Jones, D; Gschmeissner, S; Lewis, J. Hair cells without supporting cells: further studies in the ear of the zebrafish mind bomb mutant. J Neurocytol. 1999;28:837–850. [PubMed]
- Haffter, P; Granato, M; Brand, M; Mullins, MC; Hammerschmidt, M; Kane, DA; Odenthal, J; van Eeden, FJ; Jiang, YJ; Heisenberg, CP; Kelsh, RN; Furutani-Seiki, M; Vogelsang, E; Beuchle, D; Schach, U; Fabian, C; Nusslein-Volhard, C. The identification of genes with unique and essential functions in the development of the zebrafish, Danio rerio. Development. 1996;123:1–36. [PubMed]
- Hale, JE; Wuthier, RE. The mechanism of matrix vesicle formation. Studies on the composition of chondrocyte microvilli and on the effects of microfilament-perturbing agents on cellular vesiculation. J Biol Chem. 1987;262:1916–1925. [PubMed]
- Harada, Y; Sugimoto, Y. Metabolic disorder of otoconia after streptomycin intoxication. Acta Oto-Laryngol. 1977;84:65–71.
- Harada, Y; Kasuga, S; Mori, N. The process of otoconia formation in guinea pig utricular supporting cells. Acta Oto-Laryngol. 1998;118:74–79.
- Hardison, AL; Lichten, L; Banerjee-Basu, S; Becker, TS; Burgess, SM. The zebrafish gene claudinj is essential for normal ear function and important for the formation of the otoliths. Mech Dev. 2005;122:949–958. [PubMed]
- House, MG; Honrubia, V. Theoretical models for the mechanisms of benign paroxysmal positional vertigo. Audiol Neuro-Otol. 2003;8:91–99.
- Hsu, CJ. Ultrastructural study of cytochemical localization of carbonic anhydrase in the inner ear. Acta Oto-Laryngol. 1991;111:75–84.
- Huang, L; Gitschier, J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet. 1997;17:292–297. [PubMed]
- Huang, L; Kuo, YM; Gitschier, J. The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency. Nat Genet. 1999;23:329–332. [PubMed]
- Hughes, I; Blasiole, B; Huss, D; Warchol, ME; Rath, NP; Hurle, B; Ignatova, E; Dickman, JD; Thalmann, R; Levenson, R; Ornitz, DM. Otopetrin 1 is required for otolith formation in the zebrafish Danio rerio. Dev Biol. 2004;276:391–402. [PubMed]
- Hughes, I; Speck, JD; Saito, M; Schlesinger, PH; Warchol, ME; Ornitz, DM. Otopetrin 1: a novel purinergic nucleotide-gated regulator of intracellular calcium. in preparation.
- Huizing, M; Anikster, Y; Gahl, WA. Hermansky–Pudlak syndrome and related disorders of organelle formation. Traffic. 2000;1:823–835. [PubMed]
- Huizing, M; Boissy, RE; Gahl, WA. Hermansky–Pudlak syndrome: vesicle formation from yeast to man. Pigm Cell Res. 2002;15:405–419.
- Hulander, M; Kiernan, AE; Blomqvist, SR; Carlsson, P; Samuelsson, EJ; Johansson, BR; Steel, KP; Enerback, S. Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice. Development. 2003;130:2013–2025. [PubMed]
- Hurle, B; Ignatova, E; Massironi, SM; Mashimo, T; Rios, X; Thalmann, I; Thalmann, R; Ornitz, DM. Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in Otopetrin 1. Hum Mol Genet. 2003;12:777–789. [PubMed]
- Ichimiya, I; Adams, JC; Kimura, RS. Immunolocalization of Na+, K(+)–ATPase, Ca(++)–ATPase, calcium-binding proteins, and carbonic anhydrase in the guinea pig inner ear. Acta Oto-Laryngol. 1994;114:167–176.
- Ignatova, EG; Thalmann, I; Xu, B; Ornitz, DM; Thalmann, R. Molecular mechanisms underlying ectopic otoconia-like particles in the endolymphatic sac of embryonic mice. Hear Res. 2004;194:65–72. [PubMed]
- James, J; Schellens, JP; Veenhof, VB. Electron microscopy of formation of statoconia. Experientia. 1969;25:1173–1174. [PubMed]
- Johnsson, LG; Wright, CG; Preston, RE; Henry, PJ. Streptomycin-induced defects of the otoconial membrane. Acta Oto-Laryngol. 1980;89:401–406.
- Kambayashi, J; Kobayashi, T; DeMott, JE; Marcus, NY; Thalmann, I; Thalmann, R. Effect of substrate-free vascular perfusion upon cochlear potentials and glycogen of the stria vascularis. Hear Res. 1982;6:223–240. [PubMed]
- Kantheti, P; Qiao, X; Diaz, ME; Peden, AA; Meyer, GE; Carskadon, SL; Kapfhamer, D; Sufalko, D; Robinson, MS; Noebels, JL; Burmeister, M. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron. 1998;21:111–122. [PubMed]
- Kantheti, P; Diaz, ME; Peden, AE; Seong, EE; Dolan, DF; Robinson, MS; Noebels, JL; Burmeister, ML. Genetic and phenotypic analysis of the mouse mutant mh2J, an Ap3d allele caused by IAP element insertion. Mamm Genome. 2003;14:157–167. [PubMed]
- Kawamata, S; Igarashi, Y. The fine structure of the developing otolithic organs of the rat. Acta Oto-Laryngol. 1993;Suppl. 504:30–37.
- Kelsh, RN; Brand, M; Jiang, YJ; Heisenberg, CP; Lin, S; Haffter, P; Odenthal, J; Mullins, MC; van Eeden, FJ; Furutani-Seiki, M; Granato, M; Hammerschmidt, M; Kane, DA; Warga, RM; Beuchle, D; Vogelsang, L; Nusslein-Volhard, C. Zebrafish pigmentation mutations and the processes of neural crest development. Development. 1996;123:369–389. [PubMed]
- Khan, SR. Interactions between stone-forming calcific crystals and macromolecules. Urol Int. 1997;59:59–71. [PubMed]
- Khan, KM; Drescher, DG. Proteins of the gelatinous layer of the trout saccular otolithic membrane. Hear Res. 1990;43:149–158. [PubMed]
- Kido, T; Sekitani, T; Yamashita, H; Endo, S; Masumitsu, Y; Shimogori, H. Effects of carbonic anhydrase inhibitor on the otolithic organs of developing chick embryos. Am J Otolaryngol. 1991;12:191–195. [PubMed]
- Kirsch, T; Harrison, G; Golub, EE; Nah, HD. The roles of annexins and types II and X collagen in matrix vesicle-mediated mineralization of growth plate cartilage. J Biol Chem. 2000;275:35577–35583. [PubMed]
- Kiss, PJ; Knisz, J; Zhang, Y; Baltrusaitis, J; Sigmund, CD; Thalmann, R; Smith, RJ; Verpy, E; Baufi, B. Inactivation of NADPH oxidase organizer 1 results in severe imbalance. Curr Biol. 2006;16:208–213. [PubMed]
- Kitamura, K; Nomura, Y; Yagi, M; Yoshikawa, Y; Ochikubo, F. Morphological changes of cochlea in a strain of new-mutant mice. Acta Oto-Laryngol. 1991a;111:61–69.
- Kitamura, K; Yoshikawa, Y; Ochikubo, F. An ultrastructural study on vestibular sensory cells in a new-mutant mouse. Acta Oto-Laryngol. 1991b;111:1013–1020.
- Kozel, PJ; Friedman, RA; Erway, LC; Yamoah, EN; Liu, LH; Riddle, T; Duffy, JJ; Doetschman, T; Miller, ML; Cardell, EL; Shull, GE. Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2. J Biol Chem. 1998;273:18693–18696. [PubMed]
- Kozlowski, DJ; Whitfield, TT; Hukriede, NA; Lam, WK; Weinberg, ES. The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line. Dev Biol. 2005;277:27–41. [PubMed]
- Kusakari, J; Ise, I; Comegys, TH; Thalmann, I; Thalmann, R. Effect of ethacrynic acid, furosemide, and ouabain upon the endolymphatic potential and upon high energy phosphates of the stria vascularis. Laryngoscope. 1978;88:12–37. [PubMed]
- Kwak, SJ; Phillips, BT; Heck, R; Riley, BB. An expanded domain of fgf3 expression in the hindbrain of zebrafish valentino mutants results in mis-patterning of the otic vesicle. Development. 2002;129:5279–5287. [PubMed]
- Legan, PK; Lukashkina, VA; Goodyear, RJ; Kossi, M; Russell, IJ; Richardson, GP. A targeted deletion in alpha-tectorin reveals that the tectorial membrane is required for the gain and timing of cochlear feedback. Neuron. 2000;28:273–285. [PubMed]
- Leger, S; Brand, M. Fgf8 and Fgf3 are required for zebrafish ear placode induction, maintenance and inner ear patterning. Mech Dev. 2002;119:91–108. [PubMed]
- Lewis, V; Green, SA; Marsh, M; Vihko, P; Helenius, A; Mellman, I. Glycoproteins of the lysosomal membrane. J Cell Biol. 1985;100:1839–1847. [PubMed]
- Li, W; Rusiniak, ME; Chintala, S; Gautam, R; Novak, EK; Swank, RT. Murine Hermansky–Pudlak syndrome genes: regulators of lysosome-related organelles. Bioessays. 2004;26:616–628. [PubMed]
- Lim, DJ. Formation and fate of the otoconia. Scanning and transmission electron microscopy. Ann Otol Rhinol Laryngol. 1973;82:23–35. [PubMed]
- Lim, DJ. Otoconia in health and disease. A review. Ann Otol Rhinol Laryngol. 1984;Suppl. 112:17–24.
- Lim, DJ; Karabinas, C; Trune, DR. Histochemical localization of carbonic anhydrase in the inner ear. Am J Otolaryngol. 1983;4:33–42. [PubMed]
- Lins, U; Farina, M; Kurc, M; Riordan, G; Thalmann, R; Thalmann, I; Kachar, B. The otoconia of the guinea pig utricle: internal structure, surface exposure, and interactions with the filament matrix. J Struct Biol. 2000;131:67–78. [PubMed]
- Lychakov, DV; Rebane, YT. Otolith regularities. Hear Res. 2000;143:83–102. [PubMed]
- Lyon, MF. Twirler: a mutant affecting the inner ear of the house mouse. J Embryol Exp Morphol. 1958;6:105–116. [PubMed]
- Minck, DR; Erway, LC; Vorhees, CV. Preliminary findings of a reduction of otoconia in the inner ear of adult rats prenatally exposed to phenytoin. Neurotoxicol Teratol. 1989;11:307–311. [PubMed]
- Morsli, H; Tuorto, F; Choo, D; Postiglione, MP; Simeone, A; Wu, DK. Otx1 and Otx2 activities are required for the normal development of the mouse inner ear. Development. 1999;126:2335–2343. [PubMed]
- Murayama, E; Okuno, A; Ohira, T; Takagi, Y; Nagasawa, H. Molecular cloning and expression of an otolith matrix protein cDNA from the rainbow trout, Oncorhynchus mykiss. Comp Biochem Physiol Part B: Biochem Mol Biol. 2000;126:511–520.
- Murayama, E; Takagi, Y; Ohira, T; Davis, JG; Greene, MI; Nagasawa, H. Fish otolith contains a unique structural protein, otolin-1. Eur J Biochem. 2002;269:688–696. [PubMed]
- Murayama, E; Herbomel, P; Kawakami, A; Takeda, H; Nagasawa, H. Otolith matrix proteins OMP-1 and Otolin-1 are necessary for normal otolith growth and their correct anchoring onto the sensory maculae. Mech Dev. 2005;122:791–803. [PubMed]
- Nakahara, H; Bevelander, G. An electron microscope study of crystal calcium carbonate formation in the mouse otolith. Anat Rec. 1979;193:233–241. [PubMed]
- Odenthal, J; Haffter, P; Vogelsang, E; Brand, M; van Eeden, FJ; Furutani-Seiki, M; Granato, M; Hammerschmidt, M; Heisenberg, CP; Jiang, YJ; Kane, DA; Kelsh, RN; Mullins, MC; Warga, RM; Allende, ML; Weinberg, ES; Nusslein-Volhard, C. Mutations affecting the formation of the notochord in the zebrafish, Danio rerio. Development. 1996a;123:103–115. [PubMed]
- Odenthal, J; Rossnagel, K; Haffter, P; Kelsh, RN; Vogelsang, E; Brand, M; van Eeden, FJ; Furutani-Seiki, M; Granato, M; Hammerschmidt, M; Heisenberg, CP; Jiang, YJ; Kane, DA; Mullins, MC; Nusslein-Volhard, C. Mutations affecting xanthophore pigmentation in the zebrafish, Danio rerio. Development. 1996b;123:391–398. [PubMed]
- Oghalai, JS; Manolidis, S; Barth, JL; Stewart, MG; Jenkins, HA. Unrecognized benign paroxysmal positional vertigo in elderly patients. Otolaryngol-Head Neck Surg. 2000;122:630–634. [PubMed]
- Ornitz, DM; Bohne, BA; Thalmann, I; Harding, GW; Thalmann, R. Otoconial agenesis in tilted mutant mice. Hear Res. 1998;122:60–70. [PubMed]
- Paffenholz, R; Bergstrom, RA; Pasutto, F; Wabnitz, P; Munroe, RJ; Jagla, W; Heinzmann, U; Marquardt, A; Bareiss, A; Laufs, J; Russ, A; Stumm, G; Schimenti, JC; Bergstrom, DE. Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev. 2004;18:486–491. [PubMed]
- Piscopo, M; Balsamo, G; Mutone, R; Avallone, B; Marmo, F. Calbindin D28K is a component of the organic matrix of lizard Podarcis sicula otoconia. Hear Res. 2003;178:89–94. [PubMed]
- Pote, KG; Ross, MD. Each otoconia polymorph has a protein unique to that polymorph. Comp Biochem Physiol Part B: Biochem Mol Biol. 1991;98:287–295.
- Pote, KG; Hauer, CR, III; Michel, H; Shabanowitz, J; Hunt, DF; Kretsinger, RH. Otoconin-22, the major protein of aragonitic frog otoconia, is a homolog of phospholipase A2. Biochemistry. 1993;32:5017–5024. [PubMed]
- Preston, RE; Johnsson, LG; Hill, JH; Schacht, J. Incorporation of radioactive calcium into otolithic membranes and middle ear ossicles of the gerbil. Acta Oto-Laryngol. 1975;80:269–275.
- Rauch, TM. The additive effects of two mutant genes on otolith formation in mice: an animal model to assess otolith function. J Aud Res. 1979;19:259–265. [PubMed]
- Reynolds, JL; Skepper, JN; McNair, R; Kasama, T; Gupta, K; Weissberg, PL; Jahnen-Dechent, W; Shanahan, CM. Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol. 2005;16:2920–2930. [PubMed]
- Riley, BB; Grunwald, DJ. A mutation in zebrafish affecting a localized cellular function required for normal ear development. Dev Biol. 1996;179:427–435. [PubMed]
- Riley, BB; Moorman, SJ. Development of utricular otoliths, but not saccular otoliths, is necessary for vestibular function and survival in zebrafish. J Neurobiol. 2000;43:329–337. [PubMed]
- Riley, BB; Zhu, C; Janetopoulos, C; Aufderheide, KJ. A critical period of ear development controlled by distinct populations of ciliated cells in the zebrafish. Dev Biol. 1997;191:191–201. [PubMed]
- Riley, BB; Chiang, M; Farmer, L; Heck, R. The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1. Development. 1999;126:5669–5678. [PubMed]
- Rolfsen, RM; Erway, LC. Trace metals and otolith defects in mocha mice. J Hered. 1984;75:159–162. [PubMed]
- Ross, MD. Calcium ion uptake and exchange in otoconia. Adv Oto-Rhino-Laryngol. 1979;25:26–33.
- Ross, MD; Peacor, D; Johnsson, LG; Allard, LF. Observations on normal and degenerating human otoconia. Ann Otol Rhinol Laryngol. 1976;85:310–326. [PubMed]
- Sakagami, M. Role of osteopontin in the rodent inner ear as revealed by in situ hybridization. Med Electron Microsc. 2000;33:3–10. [PubMed]
- Salt, AN; Inamura, N; Thalmann, R; Vora, A. Calcium gradients in inner ear endolymph. Am J Otolaryngol. 1989;10:371–375. [PubMed]
- Sanchez-Fernandez, JM; Rivera-Pomar, JM. A scanning electron microscopy study on human otoconia genesis. Acta Oto-Laryngol. 1984;97:479–488.
- Sanchez-Fernandez, JM; Rivera-Pomar, JM; Tello, MJ. Human otoconial crystal growth. An approach from morphological and morphometric data. ORL J Otorhinolaryngol Relat Spec. 1989;51:108–115. [PubMed]
- Shiao, JC; Lin, LY; Horng, JL; Hwang, PP; Kaneko, T. How can teleostean inner ear hair cells maintain the proper association with the accreting otolith? J Comp Neurol. 2005;488:331–341. [PubMed]
- Shull, GE; Okunade, G; Liu, LH; Kozel, P; Periasamy, M; Lorenz, JN; Prasad, V. Physiological functions of plasma membrane and intracellular Ca2+ pumps revealed by analysis of null mutants. Ann N Y Acad Sci. 2003;986:453–460. [PubMed]
- Simmler, MC; Cohen-Salmon, M; El-Amraoui, A; Guillaud, L; Benichou, JC; Petit, C; Panthier, JJ. Targeted disruption of otog results in deafness and severe imbalance. Nat Genet. 2000a;24:139–143. [PubMed]
- Simmler, MC; Zwaenepoel, II; Verpy, E; Guillaud, L; Elbaz, C; Petit, C; Panthier, JJ. Twister mutant mice are defective for otogelin, a component specific to inner ear acellular membranes. Mamm Genome. 2000b;11:961–966. [PubMed]
- Sollner, C; Burghammer, M; Busch-Nentwich, E; Berger, J; Schwarz, H; Riekel, C; Nicolson, T. Control of crystal size and lattice formation by starmaker in otolith biomineralization. Science. 2003;302:282–286. [PubMed]
- Sollner, C; Schwarz, H; Geisler, R; Nicolson, T. Mutated otopetrin 1 affects the genesis of otoliths and the localization of Starmaker in zebrafish. Dev Genes Evol. 2004;214:582–590. [PubMed]
- Solomon, KS; Kudoh, T; Dawid, IB; Fritz, A. Zebrafish foxi1 mediates otic placode formation and jaw development. Development. 2003;130:929–940. [PubMed]
- Spicer, SS; Schulte, BA. Differentiation of inner ear fibrocytes according to their ion transport related activity. Hear Res. 1991;56:53–64. [PubMed]
- Sreenath, T; Thyagarajan, T; Hall, B; Longenecker, G; D’Souza, R; Hong, S; Wright, JT; MacDougall, M; Sauk, J; Kulkarni, AB. Dentin sialophosphoprotein knockout mouse teeth display widened predentin zone and develop defective dentin mineralization similar to human dentinogenesis imperfecta type III. J Biol Chem. 2003;278:24874–24880. [PubMed]
- Stevens, CB; Davies, AL; Battista, S; Lewis, JH; Fekete, DM. Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear. Dev Biol. 2003;261:149–164. [PubMed]
- Sumanas, S; Larson, JD; Miller Bever, M. Zebrafish chaperone protein GP96 is required for otolith formation during ear development. Dev Biol. 2003;261:443–455. [PubMed]
- Suzuki, H; Ikeda, K; Takasaka, T. Biological characteristics of the globular substance in the otoconial membrane of the guinea pig. Hear Res. 1995;90:212–218. [PubMed]
- Suzuki, H; Ikeda, K; Furukawa, M; Takasaka, T. P2 purinoceptor of the globular substance in the otoconial membrane of the guinea pig inner ear. Am J Physiol. 1997a;273:C1533–C1540. [PubMed]
- Suzuki, H; Ikeda, K; Takasaka, T. Age-related changes of the globular substance in the otoconial membrane of mice. Laryngoscope. 1997b;107:378–381. [PubMed]
- Tachibana, M; Morioka, H. Glucuronic acid-containing glycosaminoglycans occur in otoconia: cytochemical evidence by hyaluronidase-gold labeling. Hear Res. 1992;62:11–15. [PubMed]
- Takagi, Y; Takahashi, A. Characterization of ootolith soluble-matrix producing cells in the saccular epithelium of rainbow trout (Oncorhynchus mykiss) inner ear. Anat Rec. 1999;254:322–329. [PubMed]
- Takemura, T; Sakagami, M; Nakase, T; Kubo, T; Kitamura, Y; Nomura, S. Localization of osteopontin in the otoconial organs of adult rats. Hear Res. 1994;79:99–104. [PubMed]
- Takumida, M; Zhang, DM; Yajin, K; Harada, Y. Effect of streptomycin on the otoconial layer of the guinea pig. ORL J Otorhinolaryngol Relat Spec. 1997a;59:263–268. [PubMed]
- Takumida, M; Zhang, DM; Yajin, K; Harada, Y. Formation and fate of giant otoconia of the guinea pig following streptomycin intoxication. Acta Oto-Laryngol. 1997b;117:538–544.
- Tateda, M; Suzuki, H; Ikeda, K; Takasaka, T. pH regulation of the globular substance in the otoconial membrane of the guinea-pig inner ear. Hear Res. 1998;124:91–98. [PubMed]
- Thalmann, R; Thalmann, I. Source and role of endolymph macromolecules. Acta Oto-Laryngol. 1999;119:293–296.
- Trune, DR; Lim, DJ. The behavior and vestibular nuclear morphology of otoconia-deficient pallid mutant mice. J Neurogenet. 1983;1:53–69. [PubMed]
- Thalmann, I; Hughes, I; Tong, B; Thalmann, R. Microscale analysis of proteins in inner ear tissues and fluids with emphasis on endolymphatic sac, otoconia and organ of Corti, Electrophoresis. in press.
- Tusa, RJ. Benign paroxysmal positional vertigo. Curr Neurol Neurosci Rep. 2001;1:478–485. [PubMed]
- Verpy, E; Leibovici, M; Petit, C. Characterization of otoconin-95, the major protein of murine otoconia, provides insights into the formation of these inner ear biominerals. Proc Natl Acad Sci U S A. 1999;96:529–534. [PubMed]
- Vibert, D; Kompis, M; Hausler, R. Benign paroxysmal positional vertigo in older women may be related to osteoporosis and osteopenia. Ann Otol Rhinol Laryngol. 2003;112:885–889. [PubMed]
- Vitelli, F; Viola, A; Morishima, M; Pramparo, T; Baldini, A; Lindsay, E. TBX1 is required for inner ear morphogenesis. Hum Mol Genet. 2003;12:2041–2048. [PubMed]
- Wang, Y; Kowalski, PE; Thalmann, I; Ornitz, DM; Mager, DL; Thalmann, R. Otoconin-90, the mammalian otoconial matrix protein, contains two domains of homology to secretory phospholipase A2. Proc Natl Acad Sci U S A. 1998;95:15345–15350. [PubMed]
- Wang, W; Xu, J; Kirsch, T. Annexin-mediated Ca2+ influx regulates growth plate chondrocyte maturation and apoptosis. J Biol Chem. 2003;278:3762–3769. [PubMed]
- Welling, DB; Parnes, LS; O’Brien, B; Bakaletz, LO; Brackmann, DE; Hinojosa, R. Particulate matter in the posterior semicircular canal. Laryngoscope. 1997;107:90–94. [PubMed]
- Whitfield, TT; Granato, M; van Eeden, FJ; Schach, U; Brand, M; Furutani-Seiki, M; Haffter, P; Hammerschmidt, M; Heisenberg, CP; Jiang, YJ; Kane, DA; Kelsh, RN; Mullins, MC; Odenthal, J; Nusslein-Volhard, C. Mutations affecting development of the zebrafish inner ear and lateral line. Development. 1996;123:241–254. [PubMed]
- Wright, CG; Hubbard, DG. SEM observations on development of human otoconia during the first trimester of gestation. Acta Oto-Laryngol. 1982;94:7–18.
- Wright, CG; Hubbard, DG; Graham, JW. Absence of otoconia in a human infant. Ann Otol Rhinol Laryngol. 1979;88:779–783. [PubMed]
- Wright, CG; Rouse, RC; Johnsson, LG; Weinberg, AG; Hubbard, DG. Vaterite otoconia in two cases of otoconial membrane dysplasia. Ann Otol Rhinol Laryngol. 1982;91:193–199. [PubMed]
- Yamane, H; Imoto, T; Nakai, Y; Igarashi, M; Rask-Andersen, H. Otoconia degradation. Acta Oto-Laryngol. 1984;Suppl. 406:263–270.
- Yaoi, Y; Suzuki, M; Tomura, H; Sasayama, Y; Kikuyama, S; Tanaka, S. Molecular cloning of otoconin-22 complementary deoxyribonucleic acid in the bullfrog endolymphatic Sac: effect of calcitonin on otoconin-22 messenger ribonucleic acid levels. Endocrinology. 2003;144:3287–3296. [PubMed]
- Zwaenepoel, I; Mustapha, M; Leibovici, M; Verpy, E; Goodyear, R; Liu, XZ; Nouaille, S; Nance, WE; Kanaan, M; Avraham, KB; Tekaia, F; Loiselet, J; Lathrop, M; Richardson, G; Petit, C. Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. Proc Natl Acad Sci U S A. 2002;99:6240–6245. [PubMed]
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