Paradigms and Paradoxes: Mouse (and Human) Models of Genetic Deafness

Hughes, David C.

doi:10.1159/000259224

Cited by 8 publications

(3 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of these patients show primary abnormalities of the sensory neuroepithelia of the inner ear, as do several hearing‐impaired mouse mutants (Fekete, 1999; Gasparini et al ., 1999; Probst & Camper, 1999). In recent years, mouse mutants have played an important role in the identification of human hereditary hearing loss genes (Steel, 1995; Hughes, 1997; Fekete, 1999; Probst & Camper, 1999). To date, numerous different genetic conditions associated with hearing impairment have been described, and several of the genes involved in these forms have been mapped and identified, showing that myosin and connexin mutations and mitochondrial dysfunction can lead to deafness (Martini et al ., 1997; Steel et al ., 1997; Koehler et al ., 1999; Redowicz, 1999; Skvorak Giersch et al ., 1999).…”

Section: Discussionmentioning

confidence: 99%

Auditory and vestibular defects in the circling (ci2) rat mutant

Kaiser¹,

Fedrowitz²,

Ebert³

et al. 2001

Eur J of Neuroscience

View full text Add to dashboard Cite

The circling rat is an autosomal recessive mutant (homozygous ci2/ci2) that displays lateralized circling behaviour, locomotor hyperactivity, ataxia and stereotypic head-movement. These abnormal behaviours occur in phases or bursts either spontaneously or in response to stress. Heterozygous (ci2/+) littermates display normal spontaneous behaviours. We have previously found that ci2/ci2 rats of both genders have a lower tissue content of dopamine in the striatum ipsilateral to the preferred direction of rotation, indicating that the rats turn away from the brain hemisphere with higher striatal dopaminergic activity. In view of the similarities of the motor syndrome of the ci2/ci2 mutant rat to that of mouse deafness mutants, the present study evaluated the hearing ability of the circling rat mutant by recording brainstem auditory-evoked potentials. To test for vestibular dysfunction, a swimming test was conducted. Histological methods were used to examine the cochlear and vestibular parts of the inner ear and the cochlear and vestibular brainstem nuclei for defects. The absence of auditory-evoked potentials demonstrated a complete hearing loss in the adult ci2/ci2 mutant rat, whereas heterozygous littermates exhibited auditory-evoked potentials with thresholds resembling those of other laboratory strains. Furthermore, the mutant rats were unable to swim. Histological analysis of the inner ear of adult mutants revealed virtually complete loss of the cochlear neuroepithelium, while no such hair cell degeneration was seen in the vestibular parts of the inner ear. However, part of the vestibular hair cells showed protrusions into the endolymphatic space, suggesting alterations in the cytoskeletal architecture. The histological findings in mutant circling rats strongly indicate that the hearing loss of the mutants is of the sensory neural type, the most prevalent type of hearing loss. In the cochlear nuclei of the brain stem of mutant rats, neurons exhibited an abnormal shape, reduced size and increased density compared to controls. In contrast, no abnormal neuronal morphology was seen in the vestibular nuclei, but a significantly reduced neuronal density was found in the medial vestibular nucleus. Abnormal vestibular function would be a likely explanation for the disturbed balance of mutant rats as exemplified by the ataxia and the inability to swim, whereas the previous data on these rats strongly indicate an involvement of the basal ganglia in the abnormal circling behaviour. The genetic defect in the mutant rats, thus, results in a clinical syndrome with features also seen in human genetic disorders with deafness and hyperkinesia, making the ci2/ci2 rat an excellent model for investigating both cochlear/vestibular dysfunction and hyperkinetic movement disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Auditory and vestibular defects in the circling (ci2) rat mutant

Kaiser¹,

Fedrowitz²,

Ebert³

et al. 2001

Eur J of Neuroscience

View full text Add to dashboard Cite

show abstract

“…Other recent reviews can be consulted for further information (e.g. Steel and Brown, 1994;Steel, 1995;Petit, 1996;Hughes, 1997;Van Camp et al, 1997;Fischel-Ghodsian, 1998).…”

Section: The Mouse As a Modelmentioning

confidence: 99%

The molecular genetics of inherited deafness – current knowledge and recent advances

1998

View full text Add to dashboard Cite

“…The Immortomouse illustrates the case of specific gene insertion. Although there are few exam ples of this approach in hearing research, gene deletions, or knockouts, have recently con firmed the critical functions of genes such as the transcription factor Brn3.1, whose dele tion leads to complete loss of hair cells [3,4], the fibroblast growth factor (FGF) receptor 3. whose deletion leads to specific structural de fects in supporting-cell differentiation in the organ of Corti [5][6][7][8], and the growth factors brain-derived neurotrophic factor (BDNF) and neurotrophin-3, whose deletions lead to degeneration of specific populations of neu rons to the sensory epithelia [9], These exam ples of targeted deletion are achieved by pre paring defective DNA sequences Hanked by sequences homologous to those of the tar get genes. The aim is to inactivate the gene by inserting a piece of foreign DNA into its normal sequence.…”

Section: Transgenic Micementioning

confidence: 99%

Production of Conditionally Immortalised Cell Lines from a Transgenic Mouse

Holley

Lawlor²

1997

Audiol Neurotol

View full text Add to dashboard Cite

This review describes the H2k^btsA58 transgenic mouse (Immortomouse) and its application to the production of conditionally immortalised cell lines from sensory epithelia within the mammalian inner ear. Established cell lines should overcome many of the technical difficulties associated with experimental procedures in auditory and vestibular research. These include the limited amount of tissue available and the relatively complex and laborious dissection. Conditional immortalisation should also allow essential studies on the molecular and cellular mechanisms that govern both the differentiation of sensory cells and the development of sensory epithelia.

show abstract

Paradigms and Paradoxes: Mouse (and Human) Models of Genetic Deafness

Cited by 8 publications

References 32 publications

Auditory and vestibular defects in the circling (ci2) rat mutant

Auditory and vestibular defects in the circling (ci2) rat mutant

The molecular genetics of inherited deafness – current knowledge and recent advances

Production of Conditionally Immortalised Cell Lines from a Transgenic Mouse

Contact Info

Product

Resources

About