Tricellulin deficiency affects tight junction architecture and cochlear hair cells

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

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4036-4049
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number9
DOIs
StatePublished - Sep 3 2013

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MARVEL Domain Containing 2 Protein
Auditory Hair Cells
Tight Junctions
Endolymph
Inner Ear
Hearing Loss
Mutation
Permeability
Epithelium
Cochlear Duct
Stria Vascularis
Perilymph
Tight Junction Proteins
Poisons
Cochlea
Alopecia
Extracellular Fluid
Biotin
Electron Microscopy
Transcription Factors

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nayak, G., Lee, S. I., Yousaf, R., Edelmann, S. E., Trincot, C., Van Itallie, C. M., ... Riazuddin, S. (2013). Tricellulin deficiency affects tight junction architecture and cochlear hair cells. Journal of Clinical Investigation, 123(9), 4036-4049. https://doi.org/10.1172/JCI69031

Tricellulin deficiency affects tight junction architecture and cochlear hair cells. / Nayak, Gowri; Lee, Sue I.; Yousaf, Rizwan; Edelmann, Stephanie E.; Trincot, Claire; Van Itallie, Christina M.; Sinha, Ghanshyam P.; Rafeeq, Maria; Jones, Sherri M.; Belyantseva, Inna A.; Anderson, James M.; Forge, Andrew; Frolenkov, Gregory I.; Riazuddin, Saima.

In: Journal of Clinical Investigation, Vol. 123, No. 9, 03.09.2013, p. 4036-4049.

Research output: Contribution to journalArticle

Nayak, G, Lee, SI, Yousaf, R, Edelmann, SE, Trincot, C, Van Itallie, CM, Sinha, GP, Rafeeq, M, Jones, SM, Belyantseva, IA, Anderson, JM, Forge, A, Frolenkov, GI & Riazuddin, S 2013, 'Tricellulin deficiency affects tight junction architecture and cochlear hair cells', Journal of Clinical Investigation, vol. 123, no. 9, pp. 4036-4049. https://doi.org/10.1172/JCI69031
Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM et al. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. Journal of Clinical Investigation. 2013 Sep 3;123(9):4036-4049. https://doi.org/10.1172/JCI69031
Nayak, Gowri ; Lee, Sue I. ; Yousaf, Rizwan ; Edelmann, Stephanie E. ; Trincot, Claire ; Van Itallie, Christina M. ; Sinha, Ghanshyam P. ; Rafeeq, Maria ; Jones, Sherri M. ; Belyantseva, Inna A. ; Anderson, James M. ; Forge, Andrew ; Frolenkov, Gregory I. ; Riazuddin, Saima. / Tricellulin deficiency affects tight junction architecture and cochlear hair cells. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 9. pp. 4036-4049.
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AU - Trincot, Claire

AU - Van Itallie, Christina M.

AU - Sinha, Ghanshyam P.

AU - Rafeeq, Maria

AU - Jones, Sherri M.

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AU - Frolenkov, Gregory I.

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