Cell Type–Specific Transcriptome Analysis Reveals a Major Role for Zeb1 and miR-200b in Mouse Inner Ear Morphogenesis

Hertzano, Ronna; Elkon, Ran; Kurima, Kiyoto; Morrisson, Annie; Chan, Siaw-Lin; Sallin, Michelle; Biedlingmaier, Andrew; Darling, Douglas S.; Griffith, Andrew J.; Eisenman, David J.; Strome, Scott E.

doi:10.1371/journal.pgen.1002309

Cited by 80 publications

(96 citation statements)

References 40 publications

(51 reference statements)

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“…Frozen sections (10-μm thick) of cochlea were prepared from Cx3cr1 GFP/+ mice as described previously (59). Sections were counterstained with Alexa Fluor 568 phalloidin (Life Technologies) diluted 1:500.…”

Section: Methodsmentioning

confidence: 99%

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

Nakanishi

Kawashima

Kurima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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123

116

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The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1β secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1β blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1β. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere’s disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

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Section: Methodsmentioning

confidence: 99%

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

Nakanishi

Kawashima

Kurima

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

123

116

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“…Because the BALB QTL region is relatively small, Table 3 lists some polymorphic genes for which no cochlear role is established. Among candidates, Zeb1 is a transcription factor strongly expressed in spiral ligament (Hertzano et al 2011). One of its actions is downregulation of Cx26, a previously claimed effect of noise exposure that could depress the EP and potentially amplify injury to the organ of Corti (Nagashima et al 2010).…”

Section: Chromosome 18mentioning

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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“…At present, only a small proportion of the hair cell transcriptome has been identified. For example, various array- based methods (McDermott et al, 2007;Hertzano et al, 2011;Sinkkonen et al, 2011) and proteomic studies (Herget et al, 2013;Shin et al, 2013) have identified a few hundred hair cell markers. Therefore, we implemented a filter on the entire list of 3661 genes that required a Ͼ2-fold expression drop at 0 -24 h and a relative recovery by 168 h. This resulted in a list of 526 genes (some examples are shown in Table 1), within which were our 32 hair cell "sentinel" genes.…”

Section: Identifying Components Of the Hair Cell Transcriptomementioning

confidence: 99%

The Transcriptome of Utricle Hair Cell Regeneration in the Avian Inner Ear

Renaud

Veile

et al. 2014

J. Neurosci.

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Sensory hair cell loss is the major cause of hearing and balance disorders. Mammals are incapable of sustained hair cell regeneration, but lower vertebrates can regenerate these mechano-electrical transducers. We present the first comprehensive transcriptome (by mRNASeq) of hair cell regeneration in the chick utricle. We provide pathway and pattern annotations and correlate these with the phenotypic events that occur during regeneration. These patterns are surprisingly synchronous and highly punctuated. We show how these patterns are a new resource for identifying components of the hair cell transcriptome and identify 494 new putative hair-cell-specific genes and validate three of these (of three tested) by immunohistochemical staining. We describe many surprising new components and dynamic expression patterns, particularly within NOTCH signaling. For example, we show that HES7 is specifically expressed during utricle hair cell regeneration and closely parallels the expression of HES5. Likewise, the expression of ATOH1 is closely correlated with HEYL and the HLH inhibitory transcription factors ID1, ID2, and ID4. We investigate the correlation between fibroblast growth factor signaling and supporting cell proliferation and show that FGF20 inhibits supporting cell proliferation. We also present an analysis of 212 differentially expressed transcription factor genes in the regenerative time course that fall into nine distinct gene expression patterns, many of which correlate with phenotypic events during regeneration and represent attractive candidates for future analysis and manipulation of the regenerative program in sensory epithelia and other vertebrate neuroepithelia.

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Cell Type–Specific Transcriptome Analysis Reveals a Major Role for Zeb1 and miR-200b in Mouse Inner Ear Morphogenesis

Cited by 80 publications

References 40 publications

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy

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

The Transcriptome of Utricle Hair Cell Regeneration in the Avian Inner Ear

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