Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d.
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.
Chen
Ping
P
Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 W. 3rd St., Fifth Floor, Los Angeles, CA 90057, USA.
Zindy
Frederique
F
Abdala
Caroline
C
Liu
Feng
F
Li
Xiankui
X
Roussel
Martine F
MF
Segil
Neil
N
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004398:Dyneins; D005333:Fetus; D005455:Fluorescent Antibody Technique; D006198:Hair Cells, Auditory / Q000201:enzymology* / Q000648:ultrastructure; D034381:Hearing Loss / Q000201:enzymology* / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D009416:Nerve Regeneration / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
C493961:Cdkn1b protein, mouse; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D009218:Myosins; D004398:Dyneins