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First published online 16 August 2006
doi: 10.1242/dev.02536
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Huffington Center on Aging, Department of Otolaryngology - Head and Neck Surgery, Department of Molecular and Cellular Biology, Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Author for correspondence (e-mail:
fpereira{at}bcm.edu)
Accepted 17 July 2006
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 
-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.
Key words: COUP-TFI, Cochlea, Hair cell, Deiter's cell, Cell proliferation, Differentiation, Migration, Notch, Jag1, Hes5, Lfng, Organ culture, -secretase, DAPT, Myosin VIIa
This article has been cited by other articles:
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  A. Faedo, G. S. Tomassy, Y. Ruan, H. Teichmann, S. Krauss, S. J. Pleasure, S. Y. Tsai, M.-J. Tsai, M. Studer, and J. L. R. Rubenstein COUP-TFI Coordinates Cortical Patterning, Neurogenesis, and Laminar Fate and Modulates MAPK/ERK, AKT, and ss-Catenin Signaling Cereb Cortex, September 1, 2008; 18(9): 2117 - 2131. [Abstract] [Full Text] [PDF]
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