Abstract
Brn4, which encodes a POU transcription factor, is the gene responsible for DFN3, an X chromosome–linked, non-syndromic type of hearing loss. Brn4-deficient mice have a low endocochlear potential (EP), hearing loss, and ultrastructural alterations in spiral ligament fibrocytes, however the molecular pathology through which Brn4 deficiency causes low EP is still unclear. Mutations in the Gjb2 and Gjb6 genes encoding the gap junction proteins connexin26 (Cx26) and connexin30 (Cx30) genes, respectively, which encode gap junction proteins and are expressed in cochlear fibrocytes and non-sensory epithelial cells (i.e., cochlear supporting cells) to maintain the proper EP, are responsible for hereditary sensorineural deafness. It has been hypothesized that the gap junction in the cochlea provides an intercellular passage by which K+ is transported to maintain the EP at the high level necessary for sensory hair cell excitation. Here we analyzed the formation of gap junction plaques in cochlear supporting cells of Brn4-deficient mice at different stages by confocal microscopy and three-dimensional graphic reconstructions. Gap junctions from control mice, which are composed mainly of Cx26 and Cx30, formed linear plaques along the cell-cell junction sites with adjacent cells. These plaques formed pentagonal or hexagonal outlines of the normal inner sulcus cells and border cells. Gap junction plaques in Brn4-deficient mice did not, however, show the normal linear structure but instead formed small spots around the cell-cell junction sites. Gap junction lengths were significantly shorter, and the level of Cx26 and Cx30 was significantly reduced in Brn4-deficient mice compared with littermate controls. Thus the Brn4 mutation affected the assembly and localization of gap junction proteins at the cell borders of cochlear supporting cells, suggesting that Brn4 substantially contributes to cochlear gap junction properties to maintain the proper EP in cochleae, similar to connexin-related deafness.
Highlights
Congenital sensorineural hearing loss occurs in 1 out of every 1000 births and is one of the most common congenital diseases
These mice have severe sensorineural hearing loss together with decreased endocochlear potential (EP), fewer cytoplasmic extensions, and a reduction in the cytoplasmic volume and the number of mitochondria in the fibrocytes of the spiral ligament, no abnormalities have been observed in other organs [4]
We examined the novel molecular pathology of hereditary deafness caused by Brn4 gene deficiency in a mouse model of Deafness type 3 (DFN3)
Summary
Congenital sensorineural hearing loss occurs in 1 out of every 1000 births and is one of the most common congenital diseases. Deafness type 3 (DFN3) is the most common type of in X chromosome–linked, non-syndromic hearing loss. DFN3 is caused by mutations in Brn, which is the gene that encodes the POU domain, class 3, transcription factor 4 (POU3F4) [1]. Brn is associated with neuronal development, as radial bundle fasciculation and synapse formation are disrupted when POU3F4 is deleted from the otic mesenchyme [3]. This neuronal defect does not, explain the pathophysiology of the severe hearing loss that is present in Brn4-deficient mice and that is caused by the decreased EP [4]
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