Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1

Hurlé, Belén; Ignatova, Elena; Massironi, Sílvia Maria Gomes; Mashimo, Tomoji; Rios, Xavier; Thalmann, Isolde; Thalmann, Ruediger; Ornitz, David M.

doi:10.1093/hmg/ddg087

Cited by 117 publications

(145 citation statements)

References 53 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…In contrast, others, such as stargazer (Khan et al 2004), het (Paffenholz et al 2004), isk (Vetter et al 1996), tlt and mlh (Hurle et al 2003), Pmca2 (Kozel et al 1998), shaker/waltzer (Sun 2001), and hscy (Longo-Guess et al 2005), have not been reported as having significant bony abnormalities. It is not known, however, if some of these animals may have relatively subtle changes in the anatomy of the temporal bone that have gone unnoticed.…”

Section: Introductionmentioning

confidence: 98%

Planar Relationships of the Semicircular Canals in Two Strains of Mice

Calabrese

Hullar

2006

JARO

View full text Add to dashboard Cite

The mouse is increasingly important as a subject of vestibular research. Although many studies have focused on the vestibular responses of mice to angular rotation, the geometry of their semicircular canals has not been described. High-voltage X-ray computed tomography was used to measure the anatomy of the semicircular canals of two strains of mice, C57Bl/6J and CBA/CaJ. The horizontal plane of a stereotaxic coordinate system was defined by the midpoints of the external auditory meati and the point where the incisors emerge from the maxilla. The centroids of the lumens of the bony canals were calculated, and planes that describe the canals were fit using a least-squares regression analysis to the resulting points. Vectors normal to each regressed plane were used to represent the corresponding canal's axis of rotation, and angles of these vectors relative to skull landmarks as well as to each other were calculated. The horizontal canal of the mouse was found to be angled anteriorly upward 17.8-for CBA/CaJ and 32.6-for C57Bl/6J from the reference horizontal plane. Angles between ipsilateral canals deviated up to 12.3-from orthogonal, and angles between contralateral synergistic canals (left anterior-right posterior, right anterior-left posterior, and horizontal-horizontal) deviated from parallel by up to 14.8-. The orientations of the canals within the head as well as the orientations of the canals relative to each other were significantly different between the two strains, suggesting that care must be taken in the design and interpretation of developmental and physiologic studies involving different mouse strains.

show abstract

Section: Introductionmentioning

confidence: 98%

Planar Relationships of the Semicircular Canals in Two Strains of Mice

Calabrese

Hullar

2006

JARO

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Locally Increase Calcium and Carbonate Concentrations To Inimentioning

confidence: 94%

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

Hughes

Thalmann

et al. 2006

Brain Research

View full text Add to dashboard Cite

Human vestibular dysfunction is an increasing clinical problem. Degeneration or displacement of otoconia is a significant etiology of age-related balance disorders and Benign Positional Vertigo (BPV). In addition, commonly used antibiotics, such as aminoglycoside antibiotics, can lead to disruption of otoconial structure and function. Despite such clinical significance, relatively little information has been compiled about the development and maintenance of otoconia in humans. Recent studies in model organisms and other mammalian organ systems have revealed some of the proteins and processes required for the normal biomineralization of otoconia and otoliths in the inner ear of vertebrates. Orchestration of extracellular biomineralization requires bringing together ionic and proteinaceous components in time and space. Coordination of these events requires the normal formation of the otocyst and sensory maculae, specific secretion and localization of extracellular matrix proteins, as well as tight regulation of the endolymph ionic environment. Disruption of any of these processes can lead to the formation of abnormally shaped, or ectopic, otoconia, or otoconial agenesis. We propose that normal generation of otoconia requires a complex temporal and spatial control of developmental and biochemical events. In this review, we suggest a new hypothetical model for normal otoconial and otolith formation based on matrix vesicle mineralization in bone which we believe to be supported by information from existing mutants, morphants, and biochemical studies.

show abstract

“…het )], abbreviated het(+/−)] as well as confirmed homozygous tilted mice [(C57BL/6J-Otop1tlt)/(C57BL/6J-Otop1tlt), abbreviated tlt(−/−) (Hurle et al 2001(Hurle et al , 2003]; and heterozygous tilted (C57BL/6J)/(C57BL/6J-Otop1tlt), abbreviated tlt(+/−). The absence or presence of otoconia was confirmed postmortem in all animals by visual inspection of maculae under the dissecting microscope.…”

Section: Animals and Surgical Preparationmentioning

confidence: 96%

“…This would provide a means to evaluate the role, if any, for static loading in the generation of resting mean discharge rates and characteristics. The discovery of mouse mutations that lack macular otoconia suggests an opportunity to study unloaded macular receptors and primary afferents in detail (Bergstrom et al 1998;Hurle et al 2001Hurle et al , 2003Paffenholz et al 2004). …”

Section: Introductionmentioning

confidence: 99%

Resting Discharge Patterns of Macular Primary Afferents in Otoconia-Deficient Mice

Jones

Hoffman³

2008

JARO

View full text Add to dashboard Cite

Vestibular primary afferents in the normal mammal are spontaneously active. The consensus hypothesis states that such discharge patterns are independent of stimulation and depend instead on excitation by vestibular hair cells due to background release of synaptic neurotransmitter. In the case of otoconial sensory receptors, it is difficult to test the independence of resting discharge from natural tonic stimulation by gravity. We examined this question by studying discharge patterns of single vestibular primary afferent neurons in the absence of gravity stimulation using two mutant strains of mice that lack otoconia (OTO−; head tilt, het-Nox3, and tilted, tlt-Otop1). Our findings demonstrated that macular primary afferent neurons exhibit robust resting discharge activity in OTO− mice. Spike interval coefficient of variation (CV=SD/mean spike interval) values reflected both regular and irregular discharge patterns in OTO− mice, and the range of values for rate-normalized CV was similar to mice and other mammals with intact otoconia although there were proportionately fewer irregular fibers. Mean discharge rates were slightly higher in otoconia-deficient strains even after accounting for proportionately fewer irregular fibers [OTO−=75.4±31.1(113) vs OTO+=68.1±28.5(143) in sp/s]. These results confirm the hypothesis that resting activity in macular primary afferents occurs in the absence of ambient stimulation. The robust discharge rates are interesting in that they may reflect the presence of a functionally 'up-regulated' tonic excitatory process in the absence of natural sensory stimulation.

show abstract

Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1

Cited by 117 publications

References 53 publications

Planar Relationships of the Semicircular Canals in Two Strains of Mice

Planar Relationships of the Semicircular Canals in Two Strains of Mice

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

Resting Discharge Patterns of Macular Primary Afferents in Otoconia-Deficient Mice

Contact Info

Product

Resources

About