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TBX1 is required for normal stria vascularis and semicircular canal development.

ABSTRACT: Little is known about the role of TBX1 in post-otocyst stages of inner ear development. Here, we report on mice with a missense mutation of Tbx1 that are viable with fully developed but abnormally formed inner ears. Mutant mice are deaf due to an undeveloped stria vascularis and show vestibular dysfunction associated with abnormal semicircular canal formation. We show that TBX1 is expressed in endolymph-producing strial marginal cells and vestibular dark cells of the inner ear and is an upstream regulator of Esrrb, which previously was shown to control the developmental fate of these cells. We also show that TBX1 is expressed in sensory cells of the crista ampullaris, which may relate to the semicircular canal abnormalities observed in mutant mice. Inner ears of mutant embryos have a non-resorbed fusion plate in the posterior semicircular canal and a single ampulla connecting anterior and lateral canals. We hypothesize that the TBX1 missense mutation prevents binding with specific co-regulatory proteins. These findings reveal previously unknown functions of TBX1 during later stages of inner ear development.

SUBMITTER: Tian C

PROVIDER: S-EPMC7893642 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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TBX1 is required for normal stria vascularis and semicircular canal development.

Tian Cong C Johnson Kenneth R KR

Developmental biology 20190921 1

Little is known about the role of TBX1 in post-otocyst stages of inner ear development. Here, we report on mice with a missense mutation of Tbx1 that are viable with fully developed but abnormally formed inner ears. Mutant mice are deaf due to an undeveloped stria vascularis and show vestibular dysfunction associated with abnormal semicircular canal formation. We show that TBX1 is expressed in endolymph-producing strial marginal cells and vestibular dark cells of the inner ear and is an upstream ...[more]

PMID: 31550482

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Project description:To determine the use of multi-detector computed tomography (MDCT) in the diagnostic interpretation of superior semicircular canal dehiscence (SSCD) or thinning and its association with ear pathologies and to find whether it is an acquired condition and its association with increase in age.study was performed in a tertiary care institute present in a village, following approval of the institutional ethical committee. Retrospective review of temporal bone CT examinations performed between September 2016 and March 2017 was done. 1 mm interval axial images with sagittal and coronal reformatted images were reviewed for the presence of canal dehiscence and thinning by investigators. We characterised the Superior semicircular canal status as normal, frank dehiscence or thinning. Frank dehiscence was further classified anatomically as anterior limb, apex and posterior limb dehiscence.The patient list was then subcategorized into 5 age groups, and the prevalence of SSCD was calculated for each group.Retrospective review yielded 80 positive cases which included SSC dehiscence (N = 39) and thinning (N = 41). 80 normal scans were selected as control group retrospectively. Statistical analysis was performed to assess for differences between the groups studied. Pearson chi-square test applied. there was a significant association of SSC pathologies prevalence with increasing age (p = < 0.001). No significant relationship was found between SSCD and presence of either CSOM or Cholesteatoma (p = 0.285). Vertigo rather than Tullio phenomenon was the statistically significant complaint (p = <0.001). which brought the patient to the hospital.The SSCD and thinning belong to the same spectrum and are acquired conditions. Increasing prevalence in old age suggests it to be an acquired condition rather than a congenital one. No significant association of these condition was seen with CSOM and cholesteatoma. Vertigo is the predominat symptom bringing the patient to hospital along with Tullio phenomenon.

Project description:BACKGROUND: Sodium absorption by semicircular canal duct (SCCD) epithelial cells is thought to contribute to the homeostasis of the volume of vestibular endolymph. It was previously shown that the epithelial cells could absorb Na+ under control of a glucocorticoid hormone (dexamethasone) and the absorptive transepithelial current was blocked by amiloride. The most commonly-observed target of amiloride is the epithelial sodium channel (ENaC), comprised of the three subunits ?-, ?- and ?-ENaC. However, other cation channels have also been observed to be sensitive in a similar concentration range. The aim of this study was to determine whether SCCD epithelial cells absorb only Na+ or also K+ through an amiloride-sensitive pathway. Parasensory K+ absorption could contribute to regulation of the transduction current through hair cells, as found to occur via vestibular transitional cells [S. H. Kim and D. C. Marcus. Regulation of sodium transport in the inner ear. Hear.Res. doi:10.1016/j.heares.2011.05.003, 2011]. RESULTS: We determined the molecular and functional expression of candidate cation channels with gene array (GEO GSE6197), whole-cell patch clamp and transepithelial recordings in primary cultures of rat SCCD. ?-, ?- and ?-ENaC were all previously reported as present. The selectivity of the amiloride-sensitive transepithelial and cell membrane currents was observed in Ussing chamber and whole-cell patch clamp recordings. The cell membrane currents were carried by Na+ but not K+, but the Na+ selectivity disappeared when the cells were cultured on impermeable supports. Transepithelial currents across SCCD were also carried exclusively by Na+. CONCLUSIONS: These results are consistent with the amiloride-sensitive absorptive flux of SCCD mediated by a highly Na+-selective channel, likely ???-ENaC. These epithelial cells therefore absorb only Na+ via the amiloride-sensitive pathway and do not provide a parasensory K+ efflux from the canals via this pathway. The results further provide caution to the culture of epithelial cells on impermeable surfaces.

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TBX1 is required for normal stria vascularis and semicircular canal development.

Publications

TBX1 is required for normal stria vascularis and semicircular canal development.

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