Application of Mouse Models to Research in Hearing and Balance

Ohlemiller, Kevin K.; Jones, Sherri M.; Johnson, Kenneth R.

doi:10.1007/s10162-016-0589-1

Cited by 102 publications

(95 citation statements)

References 280 publications

(114 reference statements)

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“…Mutations in the majority of these genes result in nonsyndromic sensorineural hearing loss (SNHL), where abnormal inner ear function is the only diagnostic feature. Identification of hearing loss genes has increased our awareness of the vast clinical and genetic heterogeneity underlying this condition and has contributed greatly to our understanding of inner ear development and function through studies in animal models (Lenz and Avraham, 2011; Kazmierczak and Muller, 2012; Ohlemiller et al, 2016). Despite the large number of identified hearing loss genes, the cause of inherited SNHL still remains uncertain in many children (Sloan-Heggen et al, 2016; Mehta et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

et al. 2017

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Summary Alternative splicing contributes to gene expression dynamics in many tissues, yet its role in auditory development remains unclear. We performed whole exome sequencing in individuals with sensorineural hearing loss (SNHL) and identified pathogenic mutations in Epithelial Splicing Regulatory Protein 1 (ESRP1). Patient derived iPSCs showed alternative splicing defects that were restored upon repair of an ESRP1 mutant allele. To determine how ESRP1 mutations cause hearing loss we evaluated Esrp1−/− mouse embryos and uncovered alterations in cochlear morphogenesis, auditory hair cell differentiation and cell fate specification. Transcriptome analysis revealed impaired expression and splicing of genes with essential roles in cochlea development and auditory function. Aberrant splicing of Fgfr2 blocked stria vascularis formation due to erroneous ligand usage, which was corrected by reducing Fgf9 gene dosage. These findings implicate mutations in ESRP1 as a cause of SNHL and demonstrate the complex interplay between alternative splicing, inner ear development, and auditory function.

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Section: Introductionmentioning

confidence: 99%

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

et al. 2017

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“…For a comparison of Wnt signaling in eye vs cochlear development, readers are directed to the following review . Another unknown that is yet to be discovered is how genetic diversity among mouse models changes the relationships of these players in these gene networks …”

Section: Summary and Future Directionsmentioning

confidence: 99%

The acquisition of positional information across the radial axis of the cochlea

Munnamalai

Fekete

2019

Developmental Dynamics

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The mammalian cochlea detects sound and transmits this information to the brain. A cross section through the cochlea reveals functionally distinct epithelial domains arrayed around the circumference of a fluid‐filled duct. Six major domains include two on the roof of the duct (Reissner's membrane medially and the stria vascularis laterally) and four across the floor of the duct, including the medial and lateral halves of the sensory domain, the organ of Corti. These radial domains are distinguishable in the embryonic cochlea by differential expression of transcription factors, and we focus here on a subset of the factors that can influence cochlear fates. We then move upstream of these genes to identify which of five signaling pathways (Notch, Fgf, Wnt, Bmp, and Shh) controls their spatial patterns of expression. We link the signaling pathways to their downstream genes, separating them by their radial position, to create putative gene regulatory networks (GRNs) from two time points, before and during the time when six radial compartments arise. These GRNs offer a framework for understanding the acquisition of positional information across the radial axis of the cochlea, and to guide therapeutic approaches to repair or regenerate distinct cochlear components that may contribute to hearing loss.

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“…Important aspects of novel hearing restoration strategies including gene therapy [3], stem cells [4,5], and related intracochlear distribution nanotechnologies [6,7] are still at best in a preclinical phase.…”

Section: Introductionmentioning

confidence: 99%

Introductory Chapter - Genealogy of Audiology

Hatzopoulos¹

2017

Advances in Clinical Audiology

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Application of Mouse Models to Research in Hearing and Balance

Cited by 102 publications

References 280 publications

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development

The acquisition of positional information across the radial axis of the cochlea

Introductory Chapter - Genealogy of Audiology

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