The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear

Abstract

We have demonstrated that the phenotype of the mouse mutant sex-linked fidget ( slf ) is caused by developmental malformations of the inner ear that result in hearing loss and vestibular dysfunction. Recently, pilot mapping experiments suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on the mouse X chromosome. These mapping data, in conjunction with the observation that the vertical head-shaking phenotype of slf mutants is identical to that observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is a mutant allele of the Brn4 gene. In this paper, we have identified the nature of the slf mutation, and demonstrated that it is an X chromosomal inversion with one breakpoint close to Brn4. This inversion selectively eliminates the expression of the Brn4 gene in the developing inner ear, but not the neural tube. Finally, these results demonstrate that the slf mutation is a good mouse model for the most prevalent form of X-linked congenital deafness in man, which is associated with mutations in the human Brn4 ortholog, POU3F4.

Otic mesenchyme expression of Cre recombinase directed by the inner ear enhancer of the Brn4/Pou3f4 gene

“…A region of evolutionarily conservation was detected within a region of the human genome that is deleted in several patients with mutations in the POU3F4 gene, consistent with the hypothesis that this region is necessary for the expression of the Brn4 gene in the otic mesenchyme (Bitner-Glindzicz et al, 1995;Phippard et al, 2000). This enhancer region has been demonstrated to drive the expression of Cre recombinase in the otic mesenchyme.…”

“…This hypothesis is further supported by the sex-linked fidget allele (Pou3f4 slf ) of the gene, which is expressed in neural tube, but not the otic mesenchyme of the inner ear (Phippard et al, 2000). In this radiation-induced allele of the gene, an inversion of the central portion of the X chromosome results in a chromosomal breakpoint that lies a considerable distance upstream of the ORF, consistent with the hypothesis that an enhancer that directs expression to the otic mesenchyme lies far upstream of the ORF (Phippard et al, 2000). Mutational analyses of the human ortholog, POU3F4, demonstrated that small deletions mapping 920 kb upstream of the ORF result in a congenital hearing loss phenotype that is indistinguishable from deletions encompassing the ORF (Bitner-Glindzicz et al, 1995).…”

Molecular Genetics of Vestibular Organ Development

“…However, sex-linked fidget (slf) mice have an inversion on the X chromosome that eliminates expression of Brn4 in the developing inner ear but not the neural tube. These mice, like one of the Brn4 knockout lines, display both cochlear and vestibular deficits (Phippard et al 2000). These results provide the first evidence that a gene, expressed primarily in the periotic mesenchyme, mediates otic epithelial morphogenesis.…”

Chromosomal rearrangements are associated with higher rates of molecular evolution in mammals

“…Finally, chromosomal rearrangements may have direct positional effects. Indeed, there is experimental evidence that the rearrangements can induce changes in the expression patterns of genes located around their breakpoints (Tanimoto et al, 1999;Phippard et al, 2000;Spitz et al, 2003).…”