Sci. Aging Knowl. Environ., 7 May 2003
Vol. 2003, Issue 18, p. nw66
[DOI: 10.1126/sageke.2003.18.nw66]


Hear Today, Gone Tomorrow

Growth brake protects sound-receiving neurons

Mary Beckman;2003/18/nw66

Key Words: post-mitotic state • p19 • p27 • Kip1 • organ of Corti • apoptosis

Like a car hung up on a cliff's edge, sound-sensitive neurons perch on the brink of a deadly precipice, new research shows. The work reveals the molecular rock that stabilizes the neurons. Removing it causes the neurons to die, turning mice deaf. The results hint at a molecular basis for age-dependent hearing loss as well as other age-related neurodegeneration.

Deep inside the ear, particular sensory cells--the outer hair cells--amplify sounds coming from the eardrum. Different neurons--the inner hair cells--pick up the tones and transmit an electrochemical signal to the brain stem. Genetic defects, loud noises, or poisons, including some antibiotics and chemotherapy agents, can kill hair cells. A shortage of these irreplaceable neurons permanently impairs hearing: Without the amplifying cells, a person registers shouts but not whispers; if an individual loses the transmitters, even the loudest train whistle can't break the silence. Age-related hearing loss could result from an accumulation of environmental insults to the hair cells. In other types of neurons, a protein called Ink4d clamps down on cell division for protective purposes; if mature neurons try to split, cancer-prevention machinery induces cell suicide. Chen and colleagues wondered whether a dearth of Ink4d would harm hair cells.

The team created mice that lack both copies of the gene for Ink4d and looked for defects in the inner ear. At 5 days after birth, both mutant and normal animals carried the normal number of hair cells. By 7 weeks of age, the otherwise healthy mutant mice had lost 43% of their inner hair cells and about 15% of their outer hair cells. The researchers next tested whether the deficit impaired the animals' hearing. Using an extra-sensitive microphone to measure sound amplification by the outer hair cells, the scientists listened in the ears of normal and mutant mice. By the time they were 15 weeks old, the mutant mice had so few outer hair cells that sound was undetectable. To test the function of the inner hair cells, the team measured sound-induced neuronal activity in the brain stem. The inner hair cells required noise two to three times louder than normal in order to fire. These observations indicate that mice without Ink4d suffer gradual, severe hearing loss. Further experiments showed that mutant animals harbor fully developed hair cells undergoing division that also show early signs of suicide; this finding suggests that Ink4d prevents cell-division-induced hara-kiri in neurons that are crucial for hearing.

The results "makes it very worthwhile to look for alterations in Ink4d" in older humans with hearing problems, says neuroscientist Karl Herrup of Case Western Reserve University in Cleveland, Ohio. In addition, the work might illuminate the causes of neurodegeneration in diseases such as Alzheimer's. He likens Ink4d to an emergency brake that keeps a mature neuron from dividing, which would otherwise send the neuron to its death. Alzheimer-related abnormalities might overwhelm the safety system, "like a Humvee pushing up behind a Yugo that has its brake on." Understanding the workings of hearing cells might reveal ways to hold the brakes firm and stop cells from hurtling over the edge.

--Mary Beckman

May 7, 2003
  1. P. Chen et al., Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat. Cell Biol., 28 April 2003 [e-pub ahead of print]. [Abstract/Full Text]
Citation: M. Beckman, Hear Today, Gone Tomorrow. Sci. SAGE KE 2003, nw66 (7 May 2003);2003/18/nw66

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