Oncomodulin, an EF-Hand Ca<sup>2+</sup>Buffer, Is Critical for Maintaining Cochlear Function in Mice

Tong, Benton D.; Hornak, Aubrey J.; Maison, Stéphane F.; Ohlemiller, Kevin K.; Liberman, M. Charles; Simmons, Dwayne D.

doi:10.1523/jneurosci.3311-15.2016

Cited by 43 publications

(87 citation statements)

References 36 publications

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“…We also used utricle specimens from animals with a targeted deletion of the OCM coding sequence (OM tm1.1Ddsi ; MGI:97401) to verify the specificity and the topographic region of expression of the OCM antibodies used in this investigation (Simmons et al 2010;Tong et al 2016). These animals are designated Actb cre OCM flox/flox , and were a mixed strain with C57Bl/ 6 and 129Sv/J DNA and were approximately 60 days of age.…”

Section: Animals and Specimen Preparationmentioning

confidence: 99%

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola

Hoffman

Choy

Sultemeier

et al. 2018

JARO

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Oncomodulin (OCM, aka β-parvalbumin) is an EF-hand calcium binding protein that is expressed in a restricted set of hair cells in the peristriolar region of the mammalian utricle. In the present study, we determined the topologic distribution of OCM among hair cell phenotypes to advance our understanding of the cellular organization of the striola and the relationship of these phenotypes with characteristics of tissue polarity. The distributions of OCM-positive (OCM+) hair cells were quantified in utricles of mature C57Bl/6 mice. Immunohistochemistry was conducted using antibodies to OCM, calretinin, and β3-tubulin. Fluorophore-conjugated phalloidin was used to label hair cell stereocilia, which provided the basis for determining hair cell counts and morphologic polarizations. We found OCM expression in striolar types I and II hair cells, though the distributions were dissimilar to the native striolar type I and II distributions, favoring type I hair cells. The distribution of OCM immunoreactivity among striolar type I hair cells also reflected nonrandom distribution among type I and I phenotypes (i.e., those receiving calretinin-positive and calretinin-negative calyces, respectively). However, many OCM+ hair cells were found lateral to the striola, and within the epithelial region encompassing OCM+ hair cells, the distributions of OCM+ types I and I hair cells were similar to the native distributions of I and I in this region. Summarily, these data provide a quantitative perspective supporting the existence of different underlying factors driving the topologic expression of OCM in hair cells than those responsible for tissue polarity characteristics associated within the utricular striola, including calretinin expression in afferent calyces.

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Section: Animals and Specimen Preparationmentioning

confidence: 99%

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola

Hoffman

Choy

Sultemeier

et al. 2018

JARO

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“…Whether OM is expressed in IHCs is yet controversial. PV-3 was found to be localized in turtle hair cells and guinea pig IHCs (Hackney et al, 2003) and a minimal but significant IHC loss was found at 12 weeks in the extreme base of the Ocm −/− mutant cochlea (Tong et al, 2016), suggesting that OM might also play a role in IHCs. The current results showed that the Ocm mRNA displayed a longitudinal gradient in IHCs, while immunostaining of OM displayed extremely weakly labeling in both apical and basal IHCs.…”

Section: Discussionmentioning

confidence: 97%

“…EF-hand Ca 2+ buffers, display large differences in Ca 2+ ion binding properties and affinities (Henzl et al, 2003). OM is an OHC-specific CaBPs and critical for maintaining the function of OHCs (Tong et al, 2016). Whether OM is expressed in IHCs is yet controversial.…”

Section: Discussionmentioning

confidence: 99%

Differential Gene Expression Patterns Between Apical and Basal Inner Hair Cells Revealed by RNA-Seq

Tang

Chen

Jia

et al. 2020

Front. Mol. Neurosci.

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Tonotopic differences in the structure and physiological function, e.g., synapse number, membrane properties, Ca 2+ channels, Ca 2+ dependence of exocytosis and vesicle pool replenishment of inner hair cells (IHCs) along the longitudinal cochlear axis have recently been discovered, suggesting different gene expression patterns of IHCs. To determine whether IHCs present different gene expression patterns along the longitudinal cochlear axis, apical and basal IHCs were collected separately using the suction pipette technique from adult mouse cochleae for RNA-seq and genome-wide transcriptome analysis. We found 689 annotated genes showed more than 2-fold increase in expression. Interestingly, 93.4% of the differentially expressed genes (DEGs) was upregulated in apical IHCs. Although a subset of genes that related to IHC machinery and deafness were found to be differentially expressed, a gradient of gene expression was indeed detected in Ocm, Pvalb, Prkd1, Fbxo32, Nme2, and Sncg, which may play putative roles in the Ca 2+ buffering and survival regulation. The expression of these genes was validated by real-time quantitative PCR (RT-qPCR) or immunostaining. We conclude that IHCs from different mouse cochlear longitudinal position have different gene expression profiles. Our data might serve as a valuable resource for exploring the molecular mechanisms underlying different biological properties as well as the survival regulation of IHCs.

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“…S11); those that were not confirmed by qPCR were either not misregulated or failed the significance test, and no genes were significantly misregulated in the opposite direction. Of the genes misregulated in Mir183/96 dko homozygotes, five are known deafness genes; Myo3a, Slc26a5 and Tmc1 underlie deafness in mice and humans [24][25][26][27][28][29], while mutations in Sema3e cause deafness in people [30], and mice homozygous for a mutant allele of Ocm exhibit progressive hearing loss [31]. Table 1.…”

Section: Transcriptome Analysis Reveals Misregulation Of Gene Expressmentioning

confidence: 99%

Hearing impairment due toMir183/96/182mutations suggests both loss and gain of function effects

Lewis

Domenico

Ingham

et al. 2019

Preprint

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The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183, but the roles of these closely-linked microRNAs are as yet unknown. Here we analyse mice carrying null alleles of Mir182, and of Mir183 and Mir96 together to investigate their roles in hearing. We found that Mir183/96 heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at four weeks old. Mir182 knockout mice developed normal hearing then exhibited progressive hearing loss. We developed a new bioinformatic tool for creating a causal network connecting transcriptional regulators to their misregulated genes using publicly available data (PoPCoRN) to aid analysis of RNAseq data from the two new mutants. Our transcriptional analyses revealed significant changes in a range of other genes, but surprisingly there were fewer genes with altered expression in the organ of Corti of Mir183/96 null mice compared with our previous findings in Mir96 Dmdo mutants which have a point mutation in the miR-96 seed region. This suggests the more severe phenotype of Mir96 Dmdo mutants compared with Mir183/96 mutants, including progressive hearing loss in Mir96 Dmdo heterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets.

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Oncomodulin, an EF-Hand Ca²⁺Buffer, Is Critical for Maintaining Cochlear Function in Mice

Cited by 43 publications

References 36 publications

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola

Differential Gene Expression Patterns Between Apical and Basal Inner Hair Cells Revealed by RNA-Seq

Hearing impairment due toMir183/96/182mutations suggests both loss and gain of function effects

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Oncomodulin, an EF-Hand Ca2+Buffer, Is Critical for Maintaining Cochlear Function in Mice

Cited by 43 publications

References 36 publications

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola

Oncomodulin Expression Reveals New Insights into the Cellular Organization of the Murine Utricle Striola

Differential Gene Expression Patterns Between Apical and Basal Inner Hair Cells Revealed by RNA-Seq

Hearing impairment due toMir183/96/182mutations suggests both loss and gain of function effects

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Oncomodulin, an EF-Hand Ca²⁺Buffer, Is Critical for Maintaining Cochlear Function in Mice