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Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d
Ping Chen1, Frederique Zindy, Caroline Abdala
1Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 W. 3rd St., Fifth Floor, Los Angeles, CA 90057, USA.
Abstract:
Maintenance of the post-mitotic state in the post-natal mammalian brain is an active process that requires the cyclin-dependent kinase inhibitors (CKIs) p19Ink4d (Ink4d) and p27Kip1 (Kip1). In animals with targeted deletions of both Ink4d and Kip1, terminally differentiated, post-mitotic neurons are observed to re-enter the cell cycle, divide and undergo apoptosis. However, when either Ink4d or Kip1 alone are deleted, the post-mitotic state is maintained, suggesting a redundant role for these genes in mature neurons. In the organ of Corti--the auditory sensory epithelium of mammals--sensory hair cells and supporting cells become post-mitotic during embryogenesis and remain quiescent for the life of the animal. When lost as a result of environmental insult or genetic abnormality, hair cells do not regenerate, and this loss is a common cause of deafness in humans. Here, we report that targeted deletion of Ink4d alone is sufficient to disrupt the maintenance of the post-mitotic state of sensory hair cells in post-natal mice. In Ink4d-/- animals, hair cells are observed to aberrantly re-enter the cell cycle and subsequently undergo apoptosis, resulting in progressive hearing loss. Our results identify a novel mechanism underlying a non-syndromic form of progressive hearing loss in mice.
Insights
Loss of p19Ink4d (Ink4d) disrupts the quiescent state of auditory hair cells, causing them to re-enter the cell cycle and undergo apoptosis, leading to progressive hearing loss.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Post-mitotic neurons in the mammalian brain require cyclin-dependent kinase inhibitors (CKIs) like p19Ink4d (Ink4d) and p27Kip1 (Kip1) for quiescence.
- Loss of sensory hair cells in the organ of Corti leads to irreversible hearing loss, as these cells do not regenerate.
Purpose of the Study:
- To investigate the role of Ink4d in maintaining the post-mitotic state of sensory hair cells in the auditory system.
- To determine if Ink4d deficiency alone can cause hair cell dysfunction and hearing loss.
Main Methods:
- Utilized genetically engineered mice with targeted deletion of the Ink4d gene (Ink4d-/-).
- Examined the cell cycle status and survival of sensory hair cells in post-natal Ink4d-/- mice.
- Assessed hearing function in Ink4d-/- mice to evaluate the impact of hair cell loss.
Main Results:
- Targeted deletion of Ink4d alone disrupted the post-mitotic quiescence of sensory hair cells in post-natal mice.
- Ink4d-/- hair cells aberrantly re-entered the cell cycle and subsequently underwent apoptosis.
- This hair cell loss in Ink4d-/- mice resulted in progressive hearing loss.
Conclusions:
- Ink4d plays a critical, non-redundant role in maintaining the post-mitotic state of sensory hair cells.
- Ink4d deficiency is sufficient to cause a non-syndromic form of progressive hearing loss in mice.
- These findings reveal a novel mechanism contributing to hearing impairment and suggest potential therapeutic targets.
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