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Published on: January 9, 2019
Deafness due to degeneration of cochlear neurons in caspase-3-deficient mice
H Morishita1, T Makishima, C Kaneko
1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Abstract:
Mice that lack caspase-3, which functions in apoptosis, were generated by gene targeting and shown to undergo hearing loss. The ABR threshold of the caspase-3(-/-) mice was significantly elevated compared to that of caspase-3(+/+) mice at 15 days of age and was progressively elevated further by 30 days. Distortion product otoacoustic emissions were not detectable in caspase-3(-/-) mice at 15 days of age. Caspase-3(-/-) mice exhibited marked degeneration of spiral ganglion neurons and a loss of inner and outer hair cells in the cochlea at 30 days of age, although no such changes were apparent at 15 days. The degenerating neurons manifested features, including cytoplasmic vacuolization, distinct from those characteristic of apoptosis. Spiral ganglion neurons and cochlear hair cells thus appear to require caspase-3 for survival but not for initial development. The mapping of both the human caspase-3 gene and the locus responsible for an autosomal dominant, nonsyndromic form of hearing loss (DFNA24) to chromosome 4q35 suggests that the caspase-3(-/-) mice may represent a model of this human condition.
Insights
Mice lacking caspase-3 (a key apoptosis protein) experienced progressive hearing loss and cochlear degeneration. This suggests caspase-3 is vital for auditory neuron and hair cell survival, not initial development.
Area of Science:
- Auditory neuroscience
- Molecular biology
- Genetics
Background:
- Apoptosis plays a role in cellular homeostasis and development.
- Caspase-3 is a critical executioner protein in the apoptotic pathway.
- Hearing loss can result from the degeneration of auditory structures.
Purpose of the Study:
- To investigate the role of caspase-3 in auditory function and cochlear integrity.
- To determine if caspase-3 deficiency leads to hearing loss in mice.
- To explore the potential of caspase-3 deficient mice as a model for human hearing loss.
Main Methods:
- Gene targeting was used to generate caspase-3 knockout (caspase-3(-/-)) mice.
- Auditory Brainstem Response (ABR) thresholds were measured to assess hearing.
- Distortion Product Otoacoustic Emissions (DPOAEs) were recorded.
- Histological analysis of cochlear structures, including spiral ganglion neurons and hair cells, was performed.
Main Results:
- Caspase-3(-/-) mice exhibited significantly elevated ABR thresholds compared to wild-type mice, indicating hearing loss.
- Hearing impairment worsened progressively with age in caspase-3(-/-) mice.
- Distortion Product Otoacoustic Emissions were undetectable in caspase-3(-/-) mice.
- Marked degeneration of spiral ganglion neurons and loss of inner and outer hair cells were observed in the cochlea of caspase-3(-/-) mice by 30 days of age.
- Degenerating neurons showed features distinct from typical apoptosis.
Conclusions:
- Caspase-3 is essential for the survival of spiral ganglion neurons and cochlear hair cells.
- Caspase-3 is not required for the initial development of these auditory structures.
- Caspase-3 deficient mice may serve as a valuable model for studying autosomal dominant, nonsyndromic hearing loss (DFNA24), given the gene's locus on chromosome 4q35.
