ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells

Morozko, Eva L.; Nishio, Ayako; Ingham, Neil J.; Chandra, Rashmi; Fitzgerald, Tracy S.; Martelletti, Elisa; Borck, Guntram; Wilson, Elizabeth A.; Riordan, Gavin P.; Wangemann, Philine; Forge, Andrew; Steel, Karen P.; Liddle, Rodger A.; Friedman, Thomas B.; Belyantseva, Inna A.

doi:10.1093/hmg/ddu474

Cited by 54 publications

(60 citation statements)

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“…This fits with no other aspect of our findings, and seems to reflect cellular processes not assessed by acute examination. Notably, several published genetic impairments of tight junctions apparently do not promote EP reduction (Bahloul et al, 2009; Ben-Yosef et al, 2003; Kitajiri et al, 2014; Morozko et al, 2014; Nakano et al, 2009; Nayak et al, 2013). Young B6 mice exposed to supercritical noise levels may re-form tight junctions that are severely dysfunctional, leading to greater paracellular ion leakage and permanent EP collapse.…”

Section: Discussionmentioning

confidence: 99%

“…Both tears and holes would promote mixing of endolymph and perilymph, ostensibly exposing hair cells to toxically high K + levels, thereby magnifying hair cell and hearing loss. Such a process is supported by knockout models for tight junctional proteins such as vezatin, claudin-9, claudin-14, occludin, angulin-2 (Ildr1), and tricellulin (Bahloul et al, 2009; Ben-Yosef et al, 2003; Kitajiri et al, 2014; Morozko et al, 2014; Nakano et al, 2009; Nayak et al, 2013). Some of these models (claudin-9 and -14) show both reduced electrical resistance of tight junctions and hair cell loss, despite a normal EP.…”

Section: Introductionmentioning

confidence: 97%

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The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

et al. 2018

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The endocochlear potential (EP) provides part of the electrochemical drive for sound-driven currents through cochlear hair cells. Intense noise exposure (110 dB SPL, 2 h) differentially affects the EP in three inbred mouse strains (C57BL/6 [B6], CBA/J [CBA], BALB/cJ [BALB]) (Ohlemiller and Gagnon, 2007, Hearing Research 224:34–50; Ohlemiller et al., 2011, JARO 12:45–58). At least for mice older than 3 mos, B6 mice are unaffected, CBA mice show temporary EP reduction, and BALB mice may show temporary or permanent EP reduction. EP reduction was well correlated with histological metrics for injury to stria vascularis and spiral ligament, and little evidence was found for holes or tears in the reticular lamina that might ‘short out’ the EP. Thus we suggested that the genes and processes that underlie the strain EP differences primarily impact cochlear lateral wall, not the organ of Corti. Our previous work did not test the range of noise exposure conditions over which strain differences apply. It therefore remained possible that the relation between exposure severity and acute EP reduction simply has a higher exposure threshold in B6 mice compared to CBA and BALB. We also did not test for age dependence. It is well established that young adult animals are especially vulnerable to noise-induced permanent threshold shifts (NIPTS). It is unknown, however, whether heightened vulnerability of the lateral wall contributes to this condition. The present study extends our previous work to multiple noise exposure levels and durations, and explicitly compares young adult (6–7 wks) and older mice (>4 mos). We find that the exposure level-versus-acute EP relation is dramatically strain-dependent, such that B6 mice widely diverge from both CBA and BALB. For all three strains, however, acute EP reduction is greater in young mice. Above 110 dB SPL, all mice exhibited rapid and severe EP reduction that is likely related to tearing of the reticular lamina. By contrast, EP-versus-noise duration examined at 104 dB suggested that different processes contribute to EP reduction in young and older mice. The average EP falls to a constant level after ~7.5 min in older mice, but progressively decreases with further exposure in young mice. Confocal microscopy of organ of Corti surface preparations stained for phalloidin and zonula occludens-1 (ZO-1) indicated this corresponds to rapid loss of outer hair cells (OHCs) and formation of both holes and tears in the reticular lamina of young mice. In addition, when animals exposed at 119 dB were allowed to recover for 1 mo, only young B6 mice showed collapse of the EP to ≤5 mV. Confocal analysis suggested novel persistent loss of tight junctions in the lateral organ of Corti. This may allow paracellular leakage that permanently reduces the EP. From our other findings, we propose that noise-related lateral wall pathology in young CBA and BALB mice promotes hair cell loss and opening of the reticular lamina. The heightened vulnerability of young adult animals to noise exposure may in part reflect sp...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

et al. 2018

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“…Such leakage is normally minimized by tight junctions that line cell-cell junctions of the reticular lamina. Elimination of tight junction proteins vezatin, claudin-9, claudin-14, occludin, angulin-2 (Ildr1), or tricellulin promotes hearing loss in mice (Ben-Yosef et al 2003;Bahloul et al 2009;Nakano et al 2009;Nayak et al 2013;Kitajiri et al 2014;Morozko et al 2014). In the case of claudins-9 and -14, in vitro recordings have shown that the junctions become leaky, likely allowing K + to enter the organ of Corti and potentially killing hair cells through K + toxicity.…”

Section: Genes and Processes That Establish Or Modulate The Epmentioning

confidence: 99%

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice

Ohlemiller

Kiener

Gagnon

2016

JARO

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We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noiserelated EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.Electronic supplementary material The online version of this article

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“…In the inner ear, epithelial cells delimit the fluid-filled compartments and the tight junctions between adjacent cells prevent intermixing of the extracellular fluids (Gulley and Reese 1976; Jahnke 1975). Several tight junction proteins are found in the inner ear epithelia and variants in many of these have been associated with hearing loss in humans and mouse mutants (Ben-Yosef et al 2003; Borck et al 2011; Citi et al 1988; Gow et al 2004; Higashi et al 2013; Kitajiri et al 2004a; Kitajiri et al 2004b; Lee et al 2012; Morozko et al 2014; Nakano et al 2009; Nayak et al 2013; Raphael and Altschuler 1991; Riazuddin et al 2006; Wilcox et al 2001). …”

Section: Introductionmentioning

confidence: 99%

Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss

et al. 2015

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Pathogenic mutations of MARVELD2, encoding tricellulin, a tricelluar tight junction protein, cause autosomal recessive non-syndromic hearing loss (DFNB49) in families of Pakistan and Czech Roma origin. In fact, they are a significant cause of prelingual hearing loss in the Czech Roma, second only to GJB2 variants. Previously, we reported that mice homozygous for p.Arg497* variant of Marveld2 had a broad phenotypic spectrum, where defects were observed in the inner ear, heart, mandibular salivary gland, thyroid gland and olfactory epithelium. The current study describes the types and frequencies of MARVELD2 alleles and clinically reexamines members of DFNB49 families. We found that MARVELD2 variants are responsible for about 1.5% (95% CI: 0.8 – 2.6) of non-syndromic hearing loss in our cohort of 800 Pakistani families. The c.1331+2T>C allele is recurrent. In addition, we identified a novel large deletion in a single family, which appears to have resulted from non-allelic homologous recombination between two similar Alu short interspersed elements. Finally, we observed no other clinical manifestations co-segregating with hearing loss in DFNB49 human families, and hypothesize that the additional abnormalities in the Marveld2 mutant mouse indicates a critical non-redundant function for tricellulin in other organ systems.

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ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells

Cited by 54 publications

References 58 publications

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

The endocochlear potential as an indicator of reticular lamina integrity after noise exposure in mice

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice

Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss

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