COUP-TFI controls Notch regulation of hair cell and support cell differentiation

Development. 2006 Sep;133(18):3683-93. doi: 10.1242/dev.02536. Epub 2006 Aug 16.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blotting, Western
  • COUP Transcription Factor I / genetics
  • COUP Transcription Factor I / metabolism
  • COUP Transcription Factor I / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cochlea / cytology
  • Cochlea / embryology
  • Cochlea / metabolism
  • Dose-Response Relationship, Drug
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Developmental / drug effects
  • Glycosyltransferases / genetics
  • Glycosyltransferases / metabolism
  • Hair Cells, Auditory / cytology*
  • Hair Cells, Auditory / drug effects
  • Hair Cells, Auditory / metabolism
  • In Situ Hybridization
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Organ of Corti / cytology
  • Organ of Corti / embryology
  • Organ of Corti / metabolism
  • Polymerase Chain Reaction / methods
  • Receptors, Notch / metabolism
  • Receptors, Notch / physiology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Triglycerides / pharmacology
  • gamma-Aminobutyric Acid / analogs & derivatives
  • gamma-Aminobutyric Acid / pharmacology


  • Basic Helix-Loop-Helix Transcription Factors
  • COUP Transcription Factor I
  • Hes5 protein, mouse
  • Receptors, Notch
  • Repressor Proteins
  • Triglycerides
  • gamma-Aminobutyric Acid
  • 1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol
  • Glycosyltransferases
  • Lfng protein, mouse
  • Amyloid Precursor Protein Secretases