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First published online 16 August 2006
doi: 10.1242/dev.02536

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

Louisa S. Tang, Heather M. Alger^* and Fred A. Pereira

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

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