Indispensable role of Mdm2/p53 interaction during the embryonic and postnatal inner ear development.
p53 is a key component of a signaling network that protects cells against various stresses. As excess p53 is detrimental to cells, its levels are tightly controlled by several mechanisms. The E3 ubiquitin ligase Mdm2 is a major negative regulator of p53. The significance of balanced p53 levels in normal tissues, at different stages of lifetime, is poorly understood. We have studied in vivo how the disruption of Mdm2/p53 interaction affects the early-embryonic otic progenitor cells and their descendants, the auditory supporting cells and hair cells. We found that p53 accumulation, as a consequence of Mdm2 abrogation, is lethal to both proliferative progenitors and non-proliferating, differentiating cells. The sensitivity of postmitotic supporting cells to excess p53 decreases along maturation, suggesting that maturation-related mechanisms limit p53's transcriptional activity towards pro-apoptotic factors. We have also investigated in vitro whether p53 restricts supporting cell's regenerative capacity. Unlike in several other regenerative cellular models, p53 inactivation did not alter supporting cell's proliferative quiescence nor transdifferentiation capacity. Altogether, the postmitotic status of developing hair cells and supporting cells does not confer protection against the detrimental effects of p53 upregulation. These findings might be linked to auditory disturbances observed in developmental syndromes with inappropriate p53 upregulation.
Division of Physiology and Neuroscience, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
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Laos
Division of Physiology and Neuroscience, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
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Sulg
Division of Physiology and Neuroscience, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
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Herranen
Division of Physiology and Neuroscience, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
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Anttonen
Division of Physiology and Neuroscience, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
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Pirvola
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002453:Cell Cycle; D002470:Cell Survival; D054338:Cell Transdifferentiation; D003051:Cochlea / Q000196:embryology / Q000473:pathology; D007758:Ear, Inner / Q000196:embryology* / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; C045073:Cre recombinase; D019426:Integrases