| COUP-TFI controls Notch regulation of hair cell and support cell differentiation. | |
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MedLine Citation:
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PMID: 16914494 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The orphan nuclear receptor COUP-TFI (Nr2f1) regulates many aspects of mammalian development, but little is known about its role in cochlear hair cell and Deiter's support cell development. The COUP-TFI knockout (COUP-TFI(-/-)) has a significant increase in hair cell (HC) number in the mid-to-apical turns. The total number of hair cells is not increased over wild type, perhaps because of displaced hair cells and a shortened cochlear duct. This implicates a defect of convergent-extension in the COUP-TFI(-/-) duct. In addition, excess proliferation in the COUP-TFI(-/-) sensory epithelium indicates that the origin of the extra HCs in the apex is complex. Because loss-of-function studies of Notch signaling components have similar phenotypes, we investigated Notch regulation of hair cell differentiation in COUP-TFI(-/-) mice and confirmed misregulation of Notch signaling components, including Jag1, Hes5 and in a manner consistent with reduced Notch signaling, and correlated with increases in hair cell and support cell differentiation. The disruption of Notch signaling by a gamma-secretase inhibitor in an in vitro organ culture system of wild-type cochleae resulted in a reduction in expression of the Notch target gene Hes5 and an increase in hair cell differentiation. Importantly, inhibition of Notch activity resulted in a greater increase in hair cell differentiation in COUP-TFI(-/-) cochlear cultures than in wild-type cultures, suggesting a hypersensitivity to Notch inactivation in COUP-TFI(-/-) cochlea, particularly at the apical turn. Thus, we present evidence that reduced Notch signaling contributes to increases in hair cell and support cell differentiation in COUP-TFI(-/-) mice, and suggest that COUP-TFI is required for Notch regulation of hair cell and support cell differentiation. |
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Authors:
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Louisa S Tang; Heather M Alger; Fred A Pereira |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-08-16 |
Journal Detail:
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Title: Development (Cambridge, England) Volume: 133 ISSN: 0950-1991 ISO Abbreviation: Development Publication Date: 2006 Sep |
Date Detail:
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Created Date: 2006-08-28 Completed Date: 2007-01-04 Revised Date: 2013-05-14 |
Medline Journal Info:
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Nlm Unique ID: 8701744 Medline TA: Development Country: England |
Other Details:
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Languages: eng Pagination: 3683-93 Citation Subset: IM |
Affiliation:
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Huffington Center on Aging, Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid Precursor Protein Secretases
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genetics,
metabolism Animals Basic Helix-Loop-Helix Transcription Factors / genetics, metabolism Blotting, Western COUP Transcription Factor I / genetics, metabolism, physiology* Cell Differentiation / drug effects, genetics, physiology* Cell Proliferation / drug effects Cells, Cultured Cochlea / cytology, embryology, metabolism Dose-Response Relationship, Drug Fluorescent Antibody Technique Gene Expression Regulation, Developmental / drug effects Glycosyltransferases / genetics, metabolism Hair Cells, Auditory / cytology*, drug effects, metabolism In Situ Hybridization Mice Mice, Knockout Models, Biological Organ of Corti / cytology, embryology, metabolism Polymerase Chain Reaction / methods Receptors, Notch / metabolism, physiology* Repressor Proteins / genetics, metabolism Signal Transduction / drug effects, physiology Triglycerides / pharmacology gamma-Aminobutyric Acid / analogs & derivatives, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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DC04585/DC/NIDCD NIH HHS; R01 DC004585/DC/NIDCD NIH HHS; R55 DC004585/DC/NIDCD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Basic Helix-Loop-Helix Transcription Factors; 0/COUP Transcription Factor I; 0/Hes5 protein, mouse; 0/Receptors, Notch; 0/Repressor Proteins; 0/Triglycerides; 56-12-2/gamma-Aminobutyric Acid; 93349-26-9/1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; EC 2.4.-/Glycosyltransferases; EC 2.4.1.-/Lfng protein, mouse; EC 3.4.-/Amyloid Precursor Protein Secretases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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