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.
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Research Article

Tricellulin deficiency affects tight junction architecture and cochlear hair cells

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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Figure 9

Absence of tricellulin may lead to paracellular permeability barrier defects.

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Absence of tricellulin may lead to paracellular permeability barrier def...
Illustrations of the en face views of the proposed ultrastructural appearance of tricellular tight junctions in the reticular lamina of (B) TricR497X/R497X mice compared with that in (A) Tric+/+ mice, where the third cell is not depicted to provide the “en face” view of the junction components. The intramembranous particles formed by bicellular tight junction proteins are shown between the plasma membrane lipid bilayers. These proteins form lateral associations with junctional proteins in the adjacent cell obliterating the intercellular space. (A) At tricellular junctions in Tric+/+ mice, tricellulin and other proteins from the 3 cells associate with each other to form the central sealing elements, where the bicellular junction strands unite with it. (B) In the absence of tricellulin, the tricellular junctions are no longer continuous and the disconnected particles are possibly formed by other as yet unknown proteins. These strands are no longer able to associate with the elements of the bicellular junctions, potentially resulting in “channels” or conduits for paracellular permeability and barrier defect in the TricR497X/R497X mice. The arrows depict paracellular leak of ions or small signaling molecules through the “channels” at the tricellular junctions of TricR497X/R497X mice.