Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene.

Ronna Hertzano, Mireille Montcouquiol, Sharon Rashi-Elkeles, Rani Elkon, Raif Yücel, Wayne N. Frankel, Gideon Rechavi, Tarik Möröy, Thomas B. Friedman, Matthew W. Kelley, Karen B. Avraham
Human Molecular Genetics. 2004-07-14; 13(18): 2143-2153
DOI: 10.1093/hmg/ddh218

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1. Hum Mol Genet. 2004 Sep 15;13(18):2143-53. Epub 2004 Jul 14.

Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a
target of the Pou4f3 deafness gene.

Hertzano R(1), Montcouquiol M, Rashi-Elkeles S, Elkon R, Yücel R, Frankel WN,
Rechavi G, Möröy T, Friedman TB, Kelley MW, Avraham KB.

Author information:
(1)Department of Human Genetics and Molecular Medicine, Sackler School of
Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

Pou4f3 (Brn3.1, Brn3c) is a class IV POU domain transcription factor that has a
central function in the development of all hair cells in the human and mouse
inner ear sensory epithelia. A mutation of POU4F3 underlies human autosomal
dominant non-syndromic progressive hearing loss DFNA15. Through a comparison of
inner ear gene expression profiles of E16.5 wild-type and Pou4f3 mutant deaf mice
using a high density oligonucleotide microarray, we identified the gene encoding
growth factor independence 1 (Gfi1) as a likely in vivo target gene regulated by
Pou4f3. To validate this result, we performed semi-quantitative RT-PCR and in
situ hybridizations for Gfi1 on wild-type and Pou4f3 mutant mice. Our results
demonstrate that a deficiency of Pou4f3 leads to a statistically significant
reduction in Gfi1 expression levels and that the dynamics of Gfi1 mRNA abundance
closely follow the pattern of expression for Pou4f3. To examine the role of Gfi1
in the pathogenesis of Pou4f3-related deafness, we performed comparative analyses
of the embryonic inner ears of Pou4f3 and Gfi1 mouse mutants using
immunohistochemistry and scanning electron microscopy. The loss of Gfi1 results
in outer hair cell degeneration, which appears comparable to that observed in
Pou4f3 mutants. These results identify Gfi1 as the first downstream target of a
hair cell specific transcription factor and suggest that outer hair cell
degeneration in Pou4f3 mutants is largely or entirely a result of the loss of
expression of Gfi1.

DOI: 10.1093/hmg/ddh218
PMID: 15254021 [Indexed for MEDLINE]


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