Loss of sensory hair cells in mammals results in permanent deafness because regeneration does notoccur. The loss of regenerative ability is tied to the inability of the specialized supporting cells within theorgan of Corti to begin dividing in response to hair cell death. We have taken a developmental approach tothis problem. Our hope is that by thoroughly understanding the process by which the cells of the organ ofCorti stop dividing during embryogenesis, we will gain insight into why regeneration does not occur. In doingso, we hope to provide tools and targets for therapeutic intervention into the problem of deafness. During development of the organ of Corti, control of cell proliferation is tightly coordinated with theprocess of cell differentiation and patterning (Ruben, 1968). We have shown that the cyclin-dependentkinase inhibitor p27Klp1 is required for timing this coordination. In p27Klp1 mutant mice, cell cycle exit isdelayed, leading to supernumerary cells, a disruption of the orderly pattern of hair cell organization, anddeafness (Chen and Segil, 1999). Although p27Klp1 abundance is widely believed to be regulated at the post-transcriptional levelthrough control of protein turnover, our results indicate that transcriptional regulation of p27Klp1 is largely,though not entirely, responsible for the determining the number of cells in the mature organ. Additionalpreliminary data indicates that Notch pathway signaling may be a key player in regulating p27 transcriptionduring organ of Corti formation.
In Specific Aim 1 we analyze the role of Notch signaling in the spatial andtemporal regulation of p27Klp1 transcription during embryogenesis of the organ of Corti. In spite of the importance of p27Klp1 transcriptional regulation, we have observed that in Skp2 mutantmice, there is also a defect in cell cycle exit and organ of Corti structure. Skp2 is part of the SCF-ubiquitinligase complex that is involved in regulating p27Klp1 protein turnover.
In Specific Aim 2 we address the role ofpost-transcriptional mechanisms in the regulation of p27Klp1. Finally, in Specific Aims 3 and 4 we address the problem of regeneration directly, by studying p27Klp1regulation in postnatal supporting cells. We have recently developed techniques that allow us to purifypostnatal supporting cells and grow them in vitro. In doing so, we have discovered that perinatal supportingcells retain the capacity to reenterthe cell cycle and divide, while supporting cells from P14 mice are unableto do so. Changes in the ability of P14 supporting cells to down-regulate p27Kip1 are partly responsible forthe block to cell division that results in the lack of regeneration.
This specific aim i nvestigates the molecularbasis for the age-dependent change in p27 regulation that we hypothesize underlies the lack of regenerationin the mammalian innerear.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Abdolazimi, Yassan; Stojanova, Zlatka; Segil, Neil (2016) Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter. Development 143:841-50
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