Deformation of the Outer Hair Cells and the Accumulation of Caveolin-2 in Connexin 26 Deficient Mice.

Abstract

BACKGROUND:

Mutations in GJB2, which encodes connexin 26 (Cx26), a cochlear gap junction protein, represent a major cause of pre-lingual, non-syndromic deafness. The degeneration of the organ of Corti observed in Cx26 mutant-associated deafness is thought to be a secondary pathology of hearing loss. Here we focused on abnormal development of the organ of Corti followed by degeneration including outer hair cell (OHC) loss.

METHODS:

We investigated the crucial factors involved in late-onset degeneration and loss of OHC by ultrastructural observation, immunohistochemistry and protein analysis in our Cx26-deficient mice (Cx26f/fP0Cre).

RESULTS:

In ultrastructural observations of Cx26f/fP0Cre mice, OHCs changed shape irregularly, and several folds or notches were observed in the plasma membrane. Furthermore, the mutant OHCs had a flat surface compared with the characteristic wavy surface structure of OHCs of normal mice. Protein analysis revealed an increased protein level of caveolin-2 (CAV2) in Cx26f/fP0Cre mouse cochlea. In immunohistochemistry, a remarkable accumulation of CAV2 was observed in Cx26f/fP0Cre mice. In particular, this accumulation of CAV2 was mainly observed around OHCs, and furthermore this accumulation was observed around the shrunken site of OHCs with an abnormal hourglass-like shape.

CONCLUSIONS:

The deformation of OHCs and the accumulation of CAV2 in the organ of Corti may play a crucial role in the progression of, or secondary OHC loss in, GJB2-associated deafness. Investigation of these molecular pathways, including those involving CAV2, may contribute to the elucidation of a new pathogenic mechanism of GJB2-associated deafness and identify effective targets for new therapies.

• Authors: Takashi Anzai, Ichiro Fukunaga, Kaori Hatakeyama, Ayumi Fujimoto, Kazuma Kobayashi, Atena Nishikawa, Toru Aoki, Tetsuo Noda, Osamu Minowa, Katsuhisa Ikeda, Kazusaku Kamiya
• Journal: PloS one (PLoS One) Vol. 10 Issue 10 Pg. e0141258 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26492081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 2
• Connexins
• GJB2 protein, human
• Gjb2 protein, mouse
• Connexin 26

Topics

• Animals
• Blotting, Western
• Caveolin 2 (metabolism)
• Cell Membrane (metabolism)
• Connexin 26
• Connexins (physiology)
• Female
• Fluorescent Antibody Technique
• Hair Cells, Auditory, Outer (metabolism, pathology)
• Hearing Loss (metabolism, pathology)
• Image Processing, Computer-Assisted (methods)
• Immunoenzyme Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron, Transmission