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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 ofPOU4F3underlies human autosomal dominant non-syndromic progressive hearing loss DFNA15. Through a comparison of inner ear gene expression profiles of E16.5 wild-type andPou4f3mutant deaf mice using a high density oligonucleotide microarray, we identified the gene encoding growth factor independence 1 (Gfi1) as a likelyin vivotarget gene regulated by Pou4f3. To validate this result, we performed semi-quantitative RT–PCR andin situhybridizations forGfi1on wild-type andPou4f3mutant mice. Our results demonstrate that a deficiency ofPou4f3leads to a statistically significant reduction inGfi1expression levels and that the dynamics ofGfi1mRNA abundance closely follow the pattern of expression forPou4f3.To examine the role of Gfi1 in the pathogenesis of Pou4f3-related deafness, we performed comparative analyses of the embryonic inner ears ofPou4f3andGfi1mouse mutants using immunohistochemistry and scanning electron microscopy. The loss ofGfi1results in outer hair cell degeneration, which appears comparable to that observed inPou4f3mutants. These results identifyGfi1as the first downstream target of a hair cell specific transcription factor and suggest that outer hair cell degeneration inPou4f3mutants is largely or entirely a result of the loss of expression ofGfi1.

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