The LINC complex is essential for hearing
Henning F. Horn, … , Colin L. Stewart, Karen B. Avraham
Henning F. Horn, … , Colin L. Stewart, Karen B. Avraham
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):740-750. https://doi.org/10.1172/JCI66911.
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Research Article

The LINC complex is essential for hearing

Abstract

Hereditary hearing loss is the most common sensory deficit. We determined that progressive high-frequency hearing loss in 2 families of Iraqi Jewish ancestry was due to homozygosity for the protein truncating mutation SYNE4 c.228delAT. SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. The truncated NESP4 encoded by the families’ mutation did not localize to the ONM. NESP4 and SUN domain–containing protein 1 (SUN1), which localizes to the inner nuclear membrane (INM), are part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. Mice lacking either Nesp4 or Sun1 were evaluated for hair cell defects and hearing loss. In both Nesp4–/– and Sun1–/– mice, OHCs formed normally, but degenerated as hearing matured, leading to progressive hearing loss. The nuclei of OHCs from mutant mice failed to maintain their basal localization, potentially affecting cell motility and hence the response to sound. These results demonstrate that the LINC complex is essential for viability and normal morphology of OHCs and suggest that the position of the nucleus in sensory epithelial cells is critical for maintenance of normal hearing.

Authors

Henning F. Horn, Zippora Brownstein, Danielle R. Lenz, Shaked Shivatzki, Amiel A. Dror, Orit Dagan-Rosenfeld, Lilach M. Friedman, Kyle J. Roux, Serguei Kozlov, Kuan-Teh Jeang, Moshe Frydman, Brian Burke, Colin L. Stewart, Karen B. Avraham

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Figure 6

Nuclear localization of hair cells in Nesp4–/– and Sun1–/– mice.

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Nuclear localization of hair cells in Nesp4–/– and Sun1–/– mice. (A) W...
(A) Whole-mount preparations of cochlea at P14 demonstrate the position of the nuclei at the base of WT OHCs. In contrast, the nuclei appear toward the apical surface of the cells in Nesp4–/– OHCs. Prestin labels the OHC membrane (green), with phalloidin-labeling actin concentrated in the stereocilia (red) and DAPI staining the nuclei (blue). (B) Nuclear mislocalization of OHCs can be observed by 3D analysis of confocal stacks using Imaris software. Cochlea whole-mount preparations from WT, Nesp4–/–, and Sun1–/– mice were immunostained with Na+/K+ ATPase to label the cytoplasmic membrane (red), phalloidin to label the actin concentrated in the stereocilia (yellow), and DAPI to stain the nuclei (blue). Note location of the nuclei at the base of OHCs derived from WT mice and location of the nuclei at the apex in mutant mice. The nuclei of the IHCs have changed their position slightly. Scale bars: 15 μm.