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A "TRIC" for hearing

 
Cochlear hair cells are extremely sensitive to stress and loss of these cells is a common cause of deafness. Within the inner ear, there are 2 compositionally distinct fluids, the endolymph and the perilymph, which are compartmentalized by the epithelial cells lining the cochlea. Formation of tight junctions between epithelial cells prevents the free exchange of fluid and other molecules. Gowri Nayak and colleagues at the Cincinnati Children’s Hospital, identify a role for the tricellular tight junction protein, TRIC, in cochlear hair cell preservation. A mutation in the TRIC gene had been previously linked to hearing loss in humans; however, the mechanism of hearing loss was unknown. The authors generated a transgenic mouse model harboring the human hearing loss-associated TRIC mutation. These mice progressively lost both cochlear hair cells and hearing. The authors found that the tight junctions between cochlear epithelial cells in these mice were altered and lacked TRIC. Their data suggests that mutated TRIC creates a toxic environment in the cochlea due to free exchange between the endolymph and the perilymph due to fewer tight cell junctions. In the accompanying commentary, Karen Avraham and colleagues from Tel Aviv University point out that this new mouse model will provide insights into human TRIC-associated deafness and how tight junction function can be restored. On the left is an electron microscopy image of a freeze fracture replica showing the tricellular tight junction of an Outer Hair Cell in the mouse organ of Corti. The image on the right is a 3D reconstruction collage of confocal images of marginal cells from mouse stria vascularis stained with anti-tricellulin antibody (red) and an antibody specific to tight-junction associated protein ZO1 (green).  

Published August 27, 2013, by Corinne Williams

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Tricellulin deficiency affects tight junction architecture and cochlear hair cells
Gowri Nayak, … , Gregory I. Frolenkov, Saima Riazuddin
Gowri Nayak, … , Gregory I. Frolenkov, Saima Riazuddin
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):4036-4049. https://doi.org/10.1172/JCI69031.
View: Text | PDF
Research Article Article has an altmetric score of 18

Tricellulin deficiency affects tight junction architecture and cochlear hair cells

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Abstract

The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while the endocochlear potential and paracellular permeability of a biotin-based tracer in the stria vascularis were unaltered. Freeze-fracture electron microscopy revealed disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions in the inner ear epithelia of tricellulin-deficient mice. These ultrastructural changes may selectively affect the paracellular permeability of ions or small molecules, resulting in a toxic microenvironment for cochlear hair cells. Consistent with this hypothesis, hair cell loss was rescued in tricellulin-deficient mice when generation of normal endolymph was inhibited by a concomitant deletion of the transcription factor, Pou3f4. Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin.

Authors

Gowri Nayak, Sue I. Lee, Rizwan Yousaf, Stephanie E. Edelmann, Claire Trincot, Christina M. Van Itallie, Ghanshyam P. Sinha, Maria Rafeeq, Sherri M. Jones, Inna A. Belyantseva, James M. Anderson, Andrew Forge, Gregory I. Frolenkov, Saima Riazuddin

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A “Tric” to tighten cell-cell junctions in the cochlea for hearing
Tomohito Higashi, … , Mikio Furuse, Karen B. Avraham
Tomohito Higashi, … , Mikio Furuse, Karen B. Avraham
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):3712-3715. https://doi.org/10.1172/JCI69651.
View: Text | PDF
Commentary Article has an altmetric score of 25

A “Tric” to tighten cell-cell junctions in the cochlea for hearing

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Abstract

Tricellulin is a tricellular tight junction–associated membrane protein that controls movement of solutes at these specialized cell intersections. Mutations in the gene encoding tricellulin, TRIC, lead to nonsyndromic deafness. In this issue of the JCI, Nayak et al. created a gene-targeted knockin mouse in order to mimic the pathology of a human TRIC mutation. Deafness appears to be caused either by an increase in the K+ ion concentration around the basolateral surfaces of the outer hair cells or, alternatively, by an increase in small molecules such as ATP around the hair bundle, leading to cellular dysfunction and degeneration. Furthermore, the mice have features suggestive of syndromic hearing loss, which may have implications for care and treatment of patients harboring TRIC mutations.

Authors

Tomohito Higashi, Danielle R. Lenz, Mikio Furuse, Karen B. Avraham

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