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Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear

Milo, M., Cacciabue-Rivolta, D., Kneebone, A., Van Doorninck, H., Johnson, C., Lawoko-Kerali, G., Niranjan, M., Rivolta, M. and Holley, M. (2009) Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear. Plos One , 4 (9). Art no.e7144. ISSN 1932-6203

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We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock-down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKB beta, a dramatic increase in Akt1/PKB alpha protein and relocation of Akt1/PKB alpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing-Deafness-Renal anomaly syndrome.

Item Type: Article
Copyright, Publisher and Additional Information: © 2009 Milo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > School of Biological Sciences (Sheffield) > Department of Biomedical Science (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 16 Feb 2010 10:47
Last Modified: 04 Jun 2014 12:35
Published Version: http://dx.doi.org/10.1371/journal.pone.0007144
Status: Published
Publisher: Public Library Science
Refereed: Yes
Identification Number: 10.1371/journal.pone.0007144
URI: http://eprints.whiterose.ac.uk/id/eprint/10364

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