Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice

Nolan, Lisa S.; Chen, Jing; Gonçalves, Ana-Cláudia; Bullen, Anwen; Towers, Emily; Steel, Karen P.; Dawson, Sally J.; Gale, Jonathan E.

doi:10.1038/s41598-022-05657-2

Cited by 7 publications

(5 citation statements)

References 61 publications

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“…Recent data has established that SGs play an important role in auditory protection including from ototoxic aminoglycoside antibiotics ( Nolan et al, 2022 ; Gonçalves et al, 2019 ). Cisplatin is another common ototoxic agent and there is evidence that it might interact directly with SG proteins ( Karasawa et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, prophylactic induction of SGs with the silvestrol analogue hydroxamate (-)-9 (also known as CR-1-31-B) protected against aminoglycoside-induced hair cell death ( Gonçalves et al, 2019 ). Furthermore, recent work from our laboratory has shown that Caprin1, an RNA-binding protein and key SG component and regulator is necessary for maintenance of auditory function ( Nolan et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition

Martin

Terry

Gale

et al. 2023

Journal of Cell Science

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Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly susceptible to cisplatin. We hypothesized that cisplatin ototoxicity may be caused by cisplatin-protein interactions rather than cisplatin-DNA interactions. Two known cisplatin-binding proteins are involved in the stress granule (SG) response. SGs are a pro-survival mechanism involving formation of transient ribonucleoprotein complexes during stress. We examined the effects of cisplatin on SG dynamics and composition in cell lines derived from the cochlea and retinal pigment epithelium. Cisplatin-induced SGs are significantly diminished in size and quantity compared to arsenite-induced SGs and are persistent after 24 hours recovery. Additionally, cisplatin pre-treated cells were unable to form a typical SG response to subsequent arsenite stress. Cisplatin-induced SGs had significant reductions in the sequestration of eIF4G and proteins RACK1 and DDX3X. Live cell imaging of cisplatin-TR revealed localisation to SGs and retention for at least 24 hours. We show cisplatin-induced SGs have impaired assembly, altered composition and are persistent, providing evidence of an alternate mechanism for cisplatin-induced ototoxicity via an impaired SG response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition

Martin

Terry

Gale

et al. 2023

Journal of Cell Science

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“…Moreover, inner ear-specific deletion of Caprin1 in mice affects synapse formation between inner hair cells and spiral ganglion neurons, leading to early onset progressive hearing loss. Loss of Caprin1 impairs the ability of the cochlea to recover from noise exposure, suggesting that it is required for the maintenance of the auditory function [ 27 ]. Therefore, QKI and CAPRIN1 may be potential therapeutic targets for noise- and ototoxin-induced hearing loss.…”

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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“…Growth arrest and DNA damage 45 gamma (GADD45G) has been implicated in regulating cell survival, apoptosis, senescence, cell cycle arrest, and genomic stability (see review in [ 14 , 15 , 16 ]). Cytoplasmic activation/proliferation-associated protein-1 (CAPRIN1) is an RNA-binding protein that has been identified as a promoter of cell proliferation [ 17 ] and participates in the regulation of post-transcriptional responses to stress [ 18 , 19 , 20 ]. Therefore, we hypothesized that these two cell-cycle–associated genes are expressed in the human NP and play a role in cellular changes in the process of disc degeneration.…”

Section: Introductionmentioning

confidence: 99%

Expression of GADD45G and CAPRIN1 in Human Nucleus Pulposus: Implications for Intervertebral Disc Degeneration

Kawaguchi

Akeda

Yamada

et al. 2023

IJMS

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Marked cellular changes occur in human intervertebral disc (IVD) degeneration during disc degeneration with biochemical changes. Genome-wide analysis of the DNA methylation profile has identified 220 differentially methylated loci associated with human IVD degeneration. Among these, two cell-cycle–associated genes, growth arrest and DNA damage 45 gamma (GADD45G) and cytoplasmic activation/proliferation-associated protein-1 (CAPRIN1), were focused on. The expression of GADD45G and CAPRIN1 in human IVDs remains unknown. We aimed to examine the expression of GADD45G and CAPRIN1 in human nucleus pulposus (NP) cells and evaluate those in human NP tissues in the early and advanced stages of degeneration according to Pfirrmann magnetic resonance imaging (MRI) and histological classifications. Human NP cells were cultured as monolayers after isolation from NP tissues by sequential enzyme digestion. Total RNA was isolated, and the mRNA expression of GADD45G and CAPRIN1 was quantified using real-time polymerase chain reaction. To examine the effects of pro-inflammatory cytokines on mRNA expression, human NP cells were cultured in the presence of IL-1β. Protein expression was evaluated using Western blotting and immunohistochemistry. GADD45G and CAPRIN1 expression was identified in human NP cells at both mRNA and protein levels. The percentage of cells immunopositive for GADD45G and CAPRIN1 significantly increased according to the Pfirrmann grade. A significant correlation between the histological degeneration score and the percentage of GADD45G-immunopositive cells was identified, but not with that of CAPRIN1-immunopositive cells. The expression of cell-cycle-associated proteins (GADD45G and CAPRIN1) was enhanced in human NP cells at an advanced stage of degeneration, suggesting that it may be regulated during the progression of IVD degeneration to maintain the integrity of human NP tissues by controlling cell proliferation and apoptosis under epigenetic alteration.

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Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice

Cited by 7 publications

References 61 publications

The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition

The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition

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

Expression of GADD45G and CAPRIN1 in Human Nucleus Pulposus: Implications for Intervertebral Disc Degeneration

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