title: Regulation of p27Kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium.
abstract: Sox2 plays critical roles in cell fate specification during development and in stem cell formation; however, its role in postmitotic cells is largely unknown. Sox2 is highly expressed in supporting cells (SCs) of the postnatal mammalian auditory sensory epithelium, which unlike non-mammalian vertebrates remains quiescent even after sensory hair cell damage. Here, we induced the ablation of Sox2, specifically in SCs at three different postnatal ages (neonatal, juvenile and adult) in mice. In neonatal mice, Sox2-null inner pillar cells (IPCs, a subtype of SCs) proliferated and generated daughter cells, while other SC subtypes remained quiescent. Furthermore, p27(Kip1), a cell cycle inhibitor, was absent in Sox2-null IPCs. Similarly, upon direct deletion of p27(Kip1), p27(Kip1)-null IPCs also proliferated but retained Sox2 expression. Interestingly, cell cycle control of IPCs by Sox2-mediated expression of p27(Kip1) gradually declined with age. In addition, deletion of Sox2 or p27(Kip1) did not cause a cell fate change. Finally, chromatin immunoprecipitation with Sox2 antibodies and luciferase reporter assays with the p27(Kip1) promoter support that Sox2 directly activates p27(Kip1) transcription in postmitotic IPCs. Hence, in contrast to the well known activity of Sox2 in promoting proliferation and cell fate determination, our data demonstrate that Sox2 plays a novel role as a key upstream regulator of p27(Kip1) to maintain the quiescent state of postmitotic IPCs. Our studies suggest that manipulating Sox2 or p27(Kip1) expression is an effective approach to inducing proliferation of neonatal auditory IPCs, an initial but necessary step toward restoring hearing in mammals.
authors.affiliation: Department of Developmental Neurobiology and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Walters
authors.forename: Thomas
authors.initials: T
authors.lastname: Owen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brimble
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Steigelman
authors.forename: LingLi
authors.initials: L
authors.lastname: Zhang
authors.forename: Marcia M
authors.initials: MM
authors.lastname: Mellado Lagarde
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Valentine
authors.forename: Yiling
authors.initials: Y
authors.lastname: Yu
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Cox
authors.forename: Jian
authors.initials: J
authors.lastname: Zuo
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003051:Cochlea / Q000166:cytology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006198:Hair Cells, Auditory / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D007760:Labyrinth Supporting Cells / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C493961:Cdkn1b protein, mouse; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D025521:Tumor Suppressor Proteins; C089785:myosin VI; D000098551:Prospero-Related Homeobox 1 Protein; D013629:Tamoxifen; D050760:Cyclin-Dependent Kinase Inhibitor p27; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D018995:Myosin Heavy Chains; D001973:Bromodeoxyuridine; C031086:5-ethynyl-2'-deoxyuridine; D003857:Deoxyuridine