COUP-TFI controls Notch regulation of hair cell and support cell differentiation.
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.
Tang
Louisa S
LS
Huffington Center on Aging, Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Alger
Heather M
HM
Pereira
Fred A
FA
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D051838:COUP Transcription Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009925:Organ of Corti / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D051880:Receptors, Notch / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D051838:COUP Transcription Factor I; D016695:Glycosyltransferases; D051880:Receptors, Notch; D012097:Repressor Proteins; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C489685:Hes5 protein, mouse; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; C498392:Lfng protein, mouse