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Genomic Analysis of the Function of the Transcription Factor gata3 during Development of the Mammalian Inner Ear

Genomic Analysis of the Function of the Transcription Factor gata3 during Development of the Mammalian Inner Ear
Genomic Analysis of the Function of the Transcription Factor gata3 during Development of the Mammalian Inner Ear
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/PKBb, a dramatic increase in Akt1/PKBa protein and relocation of Akt1/PKBa from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27kip1, 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.
1932-6203
e7144
Milo, Marta
47a82354-2b0a-4f41-8330-54e5c881fdc1
Cacciabue-Rivolta, Daniela
3f077323-88e0-42af-ae06-941eaa36bb77
Kneebone, Adam
b349afdf-8e41-4500-adca-1e01fbc78507
Van Doorninck, Hikke
38c33dfe-e654-4596-8dd2-dab3411e978a
Johnson, Claire
51391180-6982-4e7c-9ee1-32860cbd6bcd
Lawoko-Kerali, Grace
88bfd851-82f0-4725-b67b-bf905d821c53
Niranjan, Mahesan
5cbaeea8-7288-4b55-a89c-c43d212ddd4f
Rivolta, Marcelo
ef164a08-dfe1-4912-a24b-055eab71a959
Holley, Matthew
41262e27-cfe4-4cf8-ae73-86ad01b6d68a
Milo, Marta
47a82354-2b0a-4f41-8330-54e5c881fdc1
Cacciabue-Rivolta, Daniela
3f077323-88e0-42af-ae06-941eaa36bb77
Kneebone, Adam
b349afdf-8e41-4500-adca-1e01fbc78507
Van Doorninck, Hikke
38c33dfe-e654-4596-8dd2-dab3411e978a
Johnson, Claire
51391180-6982-4e7c-9ee1-32860cbd6bcd
Lawoko-Kerali, Grace
88bfd851-82f0-4725-b67b-bf905d821c53
Niranjan, Mahesan
5cbaeea8-7288-4b55-a89c-c43d212ddd4f
Rivolta, Marcelo
ef164a08-dfe1-4912-a24b-055eab71a959
Holley, Matthew
41262e27-cfe4-4cf8-ae73-86ad01b6d68a

Milo, Marta, Cacciabue-Rivolta, Daniela, Kneebone, Adam, Van Doorninck, Hikke, Johnson, Claire, Lawoko-Kerali, Grace, Niranjan, Mahesan, Rivolta, Marcelo and Holley, Matthew (2009) Genomic Analysis of the Function of the Transcription Factor gata3 during Development of the Mammalian Inner Ear. PLoS ONE, 4 (9), e7144.

Record type: Article

Abstract

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/PKBb, a dramatic increase in Akt1/PKBa protein and relocation of Akt1/PKBa from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27kip1, 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.

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Published date: September 2009
Organisations: Southampton Wireless Group

Identifiers

Local EPrints ID: 268185
URI: http://eprints.soton.ac.uk/id/eprint/268185
ISSN: 1932-6203
PURE UUID: 67efa2a0-e4f0-40a3-b896-4c6678c38f13
ORCID for Mahesan Niranjan: ORCID iD orcid.org/0000-0001-7021-140X

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Date deposited: 11 Nov 2009 14:12
Last modified: 15 Mar 2024 03:29

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Contributors

Author: Marta Milo
Author: Daniela Cacciabue-Rivolta
Author: Adam Kneebone
Author: Hikke Van Doorninck
Author: Claire Johnson
Author: Grace Lawoko-Kerali
Author: Mahesan Niranjan ORCID iD
Author: Marcelo Rivolta
Author: Matthew Holley

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