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

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.

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

“…The failure to down-regulate cell cycle exit regulators is one of the reasons mammalian support cells do not proliferate in response to hair cell death (10,12,64,65). Determining the earliest changes in the expression of cell cycle regulators and mapping correlating changes in signaling pathway activations will aid in identifying candidate pathways involved in cell cycle reentry.…”

“…Knockdown of the cell cycle exit regulators Cdkn1b (p27/Kip1), p19/Ink4d, and pRb led to the initiation of cell cycle reentry and the differentiation of hair cells in injured epithelia in mice (20,21,64,76,77). Unfortunately, these ectopic hair cells cannot be maintained and eventually apoptose.…”

Essential role of retinoblastoma protein in mammalian hair cell development and hearing

“…Some negative regulators of cell proliferation have been identified, notably p27kip1 (8,9), p19ink4d (10), and pRb (11,12), which control cell-cycle exit in the inner ear. p27kip1 is primarily involved in cell-cycle arrest of inner ear sensory progenitor cells and cochlear supporting cells, whereas p19ink4d plays a role in hair cell survival.…”

Genetic and pharmacological intervention for treatment/prevention of hearing loss

“…But it appears that the mammalian cochlear sensory epithelium has lost its regenerative capacity. One possible reason for this is that the mammalian cochlea activates a number of anti-proliferation genes in both the hair cells and supporting cells of the organ of Corti as soon as the initial population of hair cells and supporting cells is established (Chen & Segil, 1999;Chen, Johnson, Zoghbi, & Segil, 2002;Chen et al, 2003;Kelley, 2002Kelley, , 2007. These genes, called oncogenes, are used in all cells of the body to prevent unregulated cell division from going out of control and becoming cancerous.…”

“…The value of this powerful technique was recently recognized by a 2007 Nobel Prize in Physiology or Medicine to Mario Capecci, Martin Evans, and Oliver Smithies, the three scientists who developed it (Nobelprize.org, 2008). Knockout mice were generated that lacked p27 kip1 , p19 Ink4d , and Rb1, three of the most wellrecognized proliferation inhibitors in cells (Chen & Segil, 1999;Chen et al, 2003;Lowenheim et al, 1999;Sage et al, 2005Sage et al, , 2006. The cochleas in mice lacking these inhibitors underwent normal embryonic development of the organ of Corti until the time when the oncogenes should have stopped proliferation.…”