Mind the gap (junction)
Almost half of the cases of deafness that occur at birth or in early childhood are due to underlying genetic defects, with mutations commonly identified within the gene encoding the cochlear gap junction protein connexin 26 (CX26). CX26-dependant hearing loss is thought to be due to a defect in development of the sensory epithelium of the auditory canal, which is a highly ordered array of mechanosensory hair cells and support cells. Surprisingly, an abundance of the highly homologous connexin, CX30, in cochlear cells does not overcome CX26-associated defects. Kazusaku Kamiya and colleagues developed murine models of CX26-depenant deafness to examine the underlying etiology of hearing loss in these animals. Loss of CX26 disrupted formation of the gap junction plaque (GJP) in embryonic animals, and reduction of CX26 in older animals promoted excessive endocytosis and GJP degradation. The accompanying three-dimensional confocal image demonstrates the cellular mosaicism of connexin expression in inner sulcus cells of Cx26f/f P0-Cre mice. Cell junctions could be clearly distinguished as normal large planar GJPs (L-GJPs), staining for both CX26 (red) and CX30 (green), or as fragmented small vesicle–like GJP (S-GJPs), that form in the absence of CX26. Cell nuclei are stained with DAPI (blue).
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Abstract
Hereditary deafness affects approximately 1 in 2,000 children. Mutations in the gene encoding the cochlear gap junction protein connexin 26 (CX26) cause prelingual, nonsyndromic deafness and are responsible for as many as 50% of hereditary deafness cases in certain populations. Connexin-associated deafness is thought to be the result of defective development of auditory sensory epithelium due to connexion dysfunction. Surprisingly, CX26 deficiency is not compensated for by the closely related connexin CX30, which is abundantly expressed in the same cochlear cells. Here, using two mouse models of CX26-associated deafness, we demonstrate that disruption of the CX26-dependent gap junction plaque (GJP) is the earliest observable change during embryonic development of mice with connexin-associated deafness. Loss of CX26 resulted in a drastic reduction in the GJP area and protein level and was associated with excessive endocytosis with increased expression of caveolin 1 and caveolin 2. Furthermore, expression of deafness-associated
Authors
Kazusaku Kamiya, Sabrina W. Yum, Nagomi Kurebayashi, Miho Muraki, Kana Ogawa, Keiko Karasawa, Asuka Miwa, Xueshui Guo, Satoru Gotoh, Yoshinobu Sugitani, Hitomi Yamanaka, Shioko Ito-Kawashima, Takashi Iizuka, Takashi Sakurai, Tetsuo Noda, Osamu Minowa, Katsuhisa Ikeda
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ISSN: 0021-9738 (print), 1558-8238 (online)