Document Detail


Regulation of p27Kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium.
MedLine Citation:
PMID:  22855803     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Zhiyong Liu; Brandon J Walters; Thomas Owen; Mark A Brimble; Katherine A Steigelman; LingLi Zhang; Marcia M Mellado Lagarde; Marcus B Valentine; Yiling Yu; Brandon C Cox; Jian Zuo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-02     Completed Date:  2012-10-15     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10530-40     Citation Subset:  IM    
Affiliation:
Department of Developmental Neurobiology and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Animals
Animals, Newborn
Bromodeoxyuridine / metabolism
Cell Cycle / drug effects,  genetics
Cell Differentiation / drug effects,  genetics
Cell Line, Transformed
Cell Proliferation / drug effects
Chromatin Immunoprecipitation
Cochlea / cytology*
Cyclin-Dependent Kinase Inhibitor p27 / genetics,  metabolism*
Deoxyuridine / analogs & derivatives,  metabolism
Gene Expression Regulation, Developmental / drug effects,  genetics
Hair Cells, Auditory / metabolism*
Homeodomain Proteins / genetics
Humans
In Situ Nick-End Labeling
Labyrinth Supporting Cells / physiology*
Luminescent Proteins / genetics
Mice
Mice, Transgenic
Myosin Heavy Chains / metabolism
Receptor, Fibroblast Growth Factor, Type 3 / genetics,  metabolism
SOXB1 Transcription Factors / genetics,  metabolism*
Tamoxifen / pharmacology
Transfection
Tumor Suppressor Proteins / genetics
Grant Support
ID/Acronym/Agency:
089015//Wellcome Trust; 1F31DC009393/DC/NIDCD NIH HHS; 1F32DC010310/DC/NIDCD NIH HHS; CA21765/CA/NCI NIH HHS; DC008800/DC/NIDCD NIH HHS; DC05168/DC/NIDCD NIH HHS; DC06471/DC/NIDCD NIH HHS; R01 DC006471/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Cdkn1b protein, mouse; 0/Homeodomain Proteins; 0/Luminescent Proteins; 0/Myosin Heavy Chains; 0/SOXB1 Transcription Factors; 0/Sox2 protein, mouse; 0/Tumor Suppressor Proteins; 0/myosin VI; 0/prospero-related homeobox 1 protein; 10540-29-1/Tamoxifen; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 59-14-3/Bromodeoxyuridine; 61135-33-9/5-ethynyl-2'-deoxyuridine; 951-78-0/Deoxyuridine; EC 2.7.10.1/Fgfr3 protein, mouse; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 3
Comments/Corrections

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