Tbx1 and Brn4regulate retinoic acid metabolic genes during cochlear morphogenesis

Braunstein, Evan M.; Monks, Dennis C.; Aggarwal, Vimla S.; Arnold, Jelena S.; Morrow, Bernice E.

doi:10.1186/1471-213x-9-31

Cited by 45 publications

(55 citation statements)

References 43 publications

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“…Two transcription factors, Tbx1 and Pou3f4, of which the latter is expressed only in the otic mesenchyme, have been implicated so far. Lack of Tbx1 or Pou3f4 in the otic mesenchyme can lead to abnormal coiling or shortening of the cochlear duct, and these two pathways have been shown to interact genetically (Phippard et al 1999;Braunstein et al 2008Braunstein et al , 2009. One possible mediator of these effects is RA, as both of these transcription factors are believed to induce expression of the RA degradation enzyme Cyp26 in the periotic mesenchyme (Braunstein et al 2009).…”

Section: Extrinsic Factorsmentioning

confidence: 99%

Molecular Mechanisms of Inner Ear Development

Kelley²

2012

Cold Spring Harbor Perspectives in Biology

177

212

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SUMMARYThe inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms.

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Section: Extrinsic Factorsmentioning

confidence: 99%

Molecular Mechanisms of Inner Ear Development

Kelley²

2012

Cold Spring Harbor Perspectives in Biology

177

212

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“…However, within the pharyngeal and periotic mesoderm, Shh promotes Tbx1 expression (Garg et al, 2001;Riccomagno et al, 2002;Yamagishi et al, 2003). Mice lacking Tbx1 in the periotic mesoderm show reduced expression of Cyp26 family members, which regulate the catabolism of retinoic acid (Braunstein et al, 2009). Consequently, retinoic acid signaling is upregulated in the otic epithelium of these mice, resulting in cochlear outgrowth defects.…”

Section: Tbx1 Expression Is Indirectly Regulated By Shhmentioning

confidence: 99%

“…The hindbrain and periotic mesenchyme are sources of other signals essential for inner ear development that are also disrupted in Shh -/-embryos (Phippard et al, 1999;Riccomagno et al, 2002;Yamagishi et al, 2003;Bok et al, 2005;Riccomagno et al, 2005;Xu et al, 2007;Braunstein et al, 2009;Liang et al, 2010). Thus, their misregulation could also explain the inner ear defects observed in Shh -/-mutants.…”

Section: Introductionmentioning

confidence: 99%

Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development

Brown

Epstein

2011

Development

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SUMMARYIn mouse embryos lacking sonic hedgehog (Shh), dorsoventral polarity within the otic vesicle is disrupted. Consequently, ventral otic derivatives, including the cochlear duct and saccule, fail to form, and dorsal otic derivatives, including the semicircular canals, endolymphatic duct and utricle, are malformed or absent. Since inner ear patterning and morphogenesis are heavily dependent on extracellular signals derived from tissues that are also compromised by the loss of Shh, the extent to which Shh signaling acts directly on the inner ear for its development is unclear. To address this question, we generated embryos in which smoothened (Smo), an essential transducer of Hedgehog (Hh) signaling, was conditionally inactivated in the otic epithelium (Smo ecko ). Ventral otic derivatives failed to form in Smo ecko embryos, whereas vestibular structures developed properly. Consistent with these findings, we demonstrate that ventral, but not dorsal, otic identity is directly dependent on Hh. The role of Hh in cochlearvestibular ganglion (cvg) formation is more complex, as both direct and indirect signaling mechanisms are implicated. Our data suggest that the loss of cvg neurons in Shh -/-animals is due, in part, to an increase in Wnt responsiveness in the otic vesicle, resulting in the ectopic expression of Tbx1 in the neurogenic domain and subsequent repression of Ngn1 transcription. A mitogenic role for Shh in cvg progenitor proliferation was also revealed in our analysis of Smo ecko embryos. Taken together, these data contribute to a better understanding of the intrinsic and extrinsic signaling properties of Shh during inner ear development.

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“…Glutamate receptor-interacting protein 1 (Grip1) is the most highly polymorphic known gene within the QTL span, although it has no published cochlear function (Dong et al 1999). Lrig3, Gli1, and Neurod4 are involved in inner ear development (Bell et al 2008;Braunstein et al 2009;Abraira et al 2010). C/EBP homologous protein 10 (Ddit3/CHOP) is expressed in the metabolically stressed stria and spiral ligament (Fujinami et al 2012).…”

Section: Chromosome 10mentioning

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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Tbx1 and Brn4regulate retinoic acid metabolic genes during cochlear morphogenesis

Cited by 45 publications

References 43 publications

Molecular Mechanisms of Inner Ear Development

Molecular Mechanisms of Inner Ear Development

Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development

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

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