Inherited diseases of the inner ear in man in the light of studies on the mouse.

Deol, M. S.

doi:10.1136/jmg.5.2.137

Cited by 114 publications

(27 citation statements)

References 93 publications

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“…Ablation of Nor-1 expression in mice results in partially penetrant hyperactive and bidirectional circling behaviors that are indicative of inner ear dysfunction (11). We have demonstrated that Nor-1 is expressed in the fusion plates of the otic vesicle and in the nonsensory epithelium of the semicircular canals of the vestibule during the critical periods of canal morphogenesis and during continual canal growth.…”

Section: Discussionmentioning

confidence: 86%

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The Nuclear Receptor Nor-1 Is Essential for Proliferation of the Semicircular Canals of the Mouse Inner Ear

Ponnio

Burton

Pereira

et al. 2002

Molecular and Cellular Biology

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Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior. During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates. After formation of the membranous labyrinth, Nor-1 expression in the vestibule is limited to nonsensory epithelial cells localized at the inner edge of the semicircular canals and to the ampullary and utricular walls. In the absence of Nor-1, the vestibular walls fuse together as normal; however, the endolymphatic fluid space in the semicircular canals is diminished and the roof of the ampulla appears flattened due to defective continual proliferative growth of the semicircular canals.The mouse inner ear develops during the second half of gestation from an otic epithelial vesicle that undergoes a complex series of shape changes to give rise to specific functional compartments including the cochlea, which comprises the auditory apparatus, and the vestibule, which is responsible for sensing motion and gravity. The endolymphatic fluid-filled membranous labyrinth is surrounded by perilymphatic fluid and is contained within an osseous structure (tympanic bone). The vestibular part of the inner ear contains two principal sets of sensory structures, the maculae (saccule and utricle), sensors of linear acceleration and gravity, and the cristae ampullaris, sensors of angular acceleration that are contained within three ampullae. Stimuli related to vestibular functions are produced by movement of the endolymphatic fluid and are recorded by sensory hair cells of the maculae and cristae.Development of the murine inner ear is initiated at E8.5 by the formation of an otic epithelial placode, which arises as a thickening of the head ectoderm between rhombomeres 5 and 6 in the hindbrain, followed by invagination and separation from the ectoderm to become a closed vesicle embedded in the head mesenchyme at E9.5. Structural perturbances begin to occur in the vesicle at E11 to 11.5 with the outgrowth of the ventral wall of the otic vesicle to form a hollow tube that gives rise to the cochlea and a dorsal extension that forms the endolymphatic duct. Cells localized in the dorsolateral walls give rise to the semicircular canals, while the medial and medioventral regions give rise to the utricle and saccule (38). Restricted and asymmetric expression patterns in the otic vesicle have been described for several genes (14, 38) at this developmental stage. These genes then participate in the regional morphogenesis of the inner ear.The semicircular canals or...

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Section: Discussionmentioning

confidence: 86%

“…This circling phenotype was never observed in the heterozygous or wild-type mice. The hyperactivity and bidirectional circling behavior are characteristics of mouse mutants with functional defects in the vestibular apparatus of the inner ear (11,23).…”

Section: Targeted Disruption Of the Nor-1 Gene In Micementioning

confidence: 99%

The Nuclear Receptor Nor-1 Is Essential for Proliferation of the Semicircular Canals of the Mouse Inner Ear

Ponnio

Burton

Pereira

et al. 2002

Molecular and Cellular Biology

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“…In newborn Kcne1 mutant mice, the phenotype of vestibular dysfunction cannot be easily discriminated by shaker/ waltzer behavior or swimming disability (Deol, 1968;Lim et al, 1978). Disruption of the Kcne1 gene leads to inner ear defects that only lead to obvious behavioral differences when the maturation of the balance and motor functions reach the stage of steady locomotion (Vetter et al, 1996).…”

Section: Methodsmentioning

confidence: 99%

Critical Roles of Transitional Cells and Na/K-ATPase in the Formation of Vestibular Endolymph

Bartolami¹,

Gaboyard²,

Quentin³

et al. 2011

J. Neurosci.

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“…Like patients suffering from JLNS, KCNE1 knockout mice are also profoundly and bilaterally deaf and exhibit an obvious vestibular dysfunction, leading to rapid head bobbing and bidirectional circling, which is referred to as Shaker-Waltzer behavior (23,40,43,75).…”

Section: Kcne1 Gene Knockout Is Associated With Deafness and Shaker-wmentioning

confidence: 99%

The multifaceted phenotype of the knockout mouse for the KCNE1 potassium channel gene

Warth

Barhanin

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Mutations of the KCNE1 gene (IsK, minK) are related to hereditary forms of cardiac arrhythmias, so-called long QT syndromes (LQT). Here we review the phenotype of a mouse model for the recessive form of LQT known as Jervell and Lange-Nielsen syndrome. KCNE1 knockout mice exhibit an enhanced QT-RR adaptability, which is probably part of the pathophysiological mechanism leading to life-threatening tachyarrhythmia in patients. Like patients, knockout mice are deaf and show vestibular symptoms due to an impaired endolymph production. Knockout mice show urinary and fecal salt wasting and volume depletion. The renal phenotype is due to diminished reabsorption of Na+ and glucose. The mice are hypokalemic and have increased aldosterone levels. Besides volume depletion, aldosterone is elevated via a set-point shift for sensing of extracellular K+ in aldosterone-secreting glomerulosa cells, which physiologically express KCNE1. In conclusion, KCNE1 knockout leads to a complex phenotype resulting from direct loss of KCNE1 and compensatory mechanisms. Murine KCNE1 physiology could be helpful for the pathophysiological understanding and perhaps gene-specific treatment of long QT patients.

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Inherited diseases of the inner ear in man in the light of studies on the mouse.

Cited by 114 publications

References 93 publications

The Nuclear Receptor Nor-1 Is Essential for Proliferation of the Semicircular Canals of the Mouse Inner Ear

The Nuclear Receptor Nor-1 Is Essential for Proliferation of the Semicircular Canals of the Mouse Inner Ear

Critical Roles of Transitional Cells and Na/K-ATPase in the Formation of Vestibular Endolymph

The multifaceted phenotype of the knockout mouse for the KCNE1 potassium channel gene

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