Conchlear inner hair cells exist transiently in the fetalBronx waltzer (bv/bv) mouse

Whitlon, Donna S.; Gabel, Carol; Zhang, Xueli

doi:10.1002/(sici)1096-9861(19960115)364:3<515::aid-cne9>3.0.co;2-7

Cited by 29 publications

(6 citation statements)

References 24 publications

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“…Analysis of the Myo6 hybridizations demonstrated that in all genotypes the cochlear apex contained IHCs, but in Srrm4 bv/bv mice the basal turn of the cochlea lacked nearly all IHCs (Figs 3A and S3A). These data are consistent with the baseto-apex progression of IHC loss in Srrm4 bv/bv mice near the time of birth (Whitlon et al, 1996). Analysis of the Srrm3 hybridizations at the cochlear apex revealed that the expression of Srrm3 was abnormally low in the IHCs (but not OHCs) of Srrm4 bv/bv mice.…”

Section: Ohcs Differ From Ihcs and Vhcs With Respect To Srrm4-indepensupporting

confidence: 82%

“…We next analyzed the survival of IHCs in Tg(DnRest);Srrm4 bv/bv mice and non-transgenic littermates at P5, the time beyond which the HC loss of Srrm4 bv/bv mice does not progress (Whitlon et al, 1996). Organs of Corti were dissected from these mice, and wholemount preparations of the isolated organs were immunostained with an antibody against the HC protein MYO7A (Figs 1F and S1H).…”

Section: Tg(dnrest) Rescues Inner Ear Function and Hcs In Srrm4 Bv/bvmentioning

confidence: 99%

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Inhibition of a transcriptional repressor rescues hearing in a splicing factor–deficient mouse

et al. 2020

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In mechanosensory hair cells (HCs) of the ear, the transcriptional repressor REST is continuously inactivated by alternative splicing of its pre-mRNA. This mechanism of REST inactivation is crucial for hearing in humans and mice. Rest is one of many pre-mRNAs whose alternative splicing is regulated by the splicing factor SRRM4; Srrm4 loss-of-function mutation in mice (Srrm4bv/bv) causes deafness, balance defects, and degeneration of all HC types other than the outer HCs (OHCs). The specific splicing alterations that drive HC degeneration in Srrm4bv/bv mice are unknown, and the mechanism underlying SRRM4-independent survival of OHCs is undefined. Here, we show that transgenic expression of a dominant-negative REST fragment in Srrm4bv/bv mice is sufficient for long-term rescue of hearing, balancing, HCs, alternative splicing of Rest, and expression of REST target genes including the Srrm4 paralog Srrm3. We also show that in HCs, SRRM3 regulates many of the same exons as SRRM4; OHCs are unique among HCs in that they transiently down-regulate Rest transcription as they mature to express Srrm3 independently of SRRM4; and simultaneous SRRM4–SRRM3 deficiency causes complete HC loss by preventing inactivation of REST in all HCs. Thus, our data reveal that REST inactivation is the primary and essential role of SRRM4 in the ear, and that OHCs differ from other HCs in the SRRM4-independent expression of the functionally SRRM4-like splicing factor SRRM3.

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Section: Ohcs Differ From Ihcs and Vhcs With Respect To Srrm4-indepensupporting

confidence: 82%

Section: Tg(dnrest) Rescues Inner Ear Function and Hcs In Srrm4 Bv/bvmentioning

confidence: 99%

Inhibition of a transcriptional repressor rescues hearing in a splicing factor–deficient mouse

et al. 2020

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“…The bv mutation has long been noted to affect IHCs more severely than OHCs (Whitlon et al, 1996;Sobkowicz et al, 2002). SRRM4 is expressed in both IHCs and OHCs in wildtype mice, and absent from both cell types in bv mice (Nakano et al, 2012).…”

Section: Srrm4mentioning

confidence: 99%

Alternative splicing in shaping the molecular landscape of the cochlea

Kim

Koo²,

Bok³

2023

Front. Cell Dev. Biol.

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The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained.

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“…It displays RNA-binding activity and regulates a network of brain-specific exons in genes with important function for neural cell differentiation [ 62 ]. Bronx waltzer ( bv ) mice show degeneration of cochlear inner hair cells, defective synaptogenesis, deafness, and impaired balance [ 63 , 64 , 65 ]. Positional cloning maps the bv mutation to the Srrm4 / nSR100 locus, and transcriptomic analysis indicates that loss of Srrm4 specifically disrupts alternative splicing events in the inner ear [ 28 ].…”

Section: Rbp-mediated Post-transcriptional Regulation In Inner Ear Ha...mentioning

confidence: 99%

Emerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration

Shi

Cheng

Saquet

et al. 2022

IJMS

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RNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein isoforms as well as in the maintenance of protein homeostasis. The inner ear is a bi-functional organ, with the cochlea and the vestibular system required for hearing and for maintaining balance, respectively. It is relatively well documented that transcription factors and signaling pathways are critically involved in the formation of inner ear structures and in the development of hair cells. Accumulating evidence highlights emerging functions of RBPs in the post-transcriptional regulation of inner ear development and hair cell function. Importantly, mutations of splicing factors of the RBP family and defective alternative splicing, which result in inappropriate expression of protein isoforms, lead to deafness in both animal models and humans. Because RBPs are critical regulators of cell proliferation and differentiation, they present the potential to promote hair cell regeneration following noise- or ototoxin-induced damage through mitotic and non-mitotic mechanisms. Therefore, deciphering RBP-regulated events during inner ear development and hair cell regeneration can help define therapeutic strategies for treatment of hearing loss. In this review, we outline our evolving understanding of the implications of RBPs in hair cell formation and hearing disease with the aim of promoting future research in this field.

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Conchlear inner hair cells exist transiently in the fetalBronx waltzer (bv/bv) mouse

Cited by 29 publications

References 24 publications

Inhibition of a transcriptional repressor rescues hearing in a splicing factor–deficient mouse

Inhibition of a transcriptional repressor rescues hearing in a splicing factor–deficient mouse

Alternative splicing in shaping the molecular landscape of the cochlea

Emerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration

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