Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction

• Published in: Journal of neurochemistry Vol. 112; no. 6; pp. 1513 - 1526
• Main Authors: Sulg, Marilin, Kirjavainen, Anna, Pajusola, Katri, Bueler, Hansruedi, Ylikoski, Jukka, Laiho, Marikki, Pirvola, Ulla
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-03-2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Adenoviridae - physiology; Adrenals. Interrenals; Adrenomedullary hormones. Regulation; Animals; Animals, Newborn; Biological and medical sciences; Calbindins; Cell cycle; Cell Cycle - drug effects; Cell Cycle - physiology; cell cycle re-entry; cell death; Cell Differentiation - drug effects; Cell Differentiation - genetics; Deoxyuridine - analogs & derivatives; Deoxyuridine - metabolism; DNA damage; DNA Damage - physiology; Ear, Inner - cytology; Ears & hearing; Fundamental and applied biological sciences. Psychology; Genotype & phenotype; Green Fluorescent Proteins - genetics; Imidazoles - pharmacology; inner ear hair cell; Isolated neuron and nerve. Neuroglia; Ki-67 Antigen - metabolism; Mechanoreceptors - physiology; Mice; Mice, Knockout; Neurology; nutlin-3a; Organ Culture Techniques; p53; Parvalbumins - genetics; Parvalbumins - metabolism; Piperazines - pharmacology; S100 Calcium Binding Protein G - genetics; S100 Calcium Binding Protein G - metabolism; Sensory perception; Time Factors; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects; Up-Regulation - genetics; Up-Regulation - physiology; Vertebrates: endocrinology; Vertebrates: nervous system and sense organs; Viral Tropism - genetics; Viral Tropism - physiology; Human; Induction; DNA damage; Inactivation; Survival; Outer hair cell; Inner ear; Organ of hearing; p53; Phenotype; Sensitivity; Postnatal; cell cycle re-entry; inner ear hair cell; Cell death; S Phase; Cell cycle; Cochlea; Inner hair cell; nutlin-3a
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06563.x

J. Neurochem. (2010) 112, 1513-1526. Previous studies have shown that the maintenance of post-mitotic state is critical for the life-long survival of the inner ear mechanosensory cells, the hair cells. A general concept is that differentiated, post-mitotic cells rapidly die following cell cycle re-entry. Here we have compared the response of postnatal cochlear (auditory) and utricular (balance) hair cells to forced cell cycle reactivation and p53 up-regulation. Forced S-phase entry was triggered through the human papillomavirus-16 E7 oncogene misexpression in explant cultures. It induced DNA damage and p53 induction in cochlear outer hair cells and these cells were rapidly lost, before entry into mitosis. The death was attenuated by p53 inactivation. In contrast, despite DNA damage and p53 induction, utricular hair cells showed longer term survival and a proportion of them progressed into mitosis. Consistently, pharmacological elevation of p53 levels by nutlin-3a led to a death-prone phenotype of cochlear outer hair cells, while other hair cell populations were death-resistant. These data have important clinical implications as they show the importance of p53 in sensory cells that are essential in hearing function.