Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d

Nat Cell Biol. 2003 May;5(5):422-6. doi: 10.1038/ncb976.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Caspase 3
  • Caspases / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Division / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p19
  • Cyclin-Dependent Kinase Inhibitor p27
  • Dyneins
  • Fetus
  • Fluorescent Antibody Technique
  • Hair Cells, Auditory / enzymology*
  • Hair Cells, Auditory / ultrastructure
  • Hearing Loss / enzymology*
  • Hearing Loss / genetics*
  • Homeostasis / genetics
  • Mice
  • Mice, Knockout
  • Myosin VIIa
  • Myosins / metabolism
  • Nerve Regeneration / genetics*
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics


  • Cdkn1b protein, mouse
  • Cdkn2d protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p19
  • MYO7A protein, human
  • Myo7a protein, mouse
  • Myosin VIIa
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Myosins
  • Dyneins