Activation of cell death pathways in the inner ear of the aging CBA/J mouse

Sha, Su Hua; Chen, Fu Quan; Schacht, Jochen

doi:10.1016/j.heares.2009.04.019

Cited by 67 publications

(65 citation statements)

References 44 publications

(57 reference statements)

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“…For example, it has been demonstrated that apoptosis occurs in outer hair cells in mice displaying age-related HL. 25 Recently, a report was published implicating apoptosis in monogenic HL. Overexpression of TJP2 leads to altered expression of apoptosis-related genes, ultimately causing HL.…”

Section: Discussionmentioning

confidence: 99%

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

et al. 2011

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DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. Keywords: tumor suppressor; hearing loss; apoptosis; dfna5; cancer; GSEA INTRODUCTION DFNA5 first was discovered in a Dutch family with autosomal dominant hearing loss (HL). 1 Not much was known concerning its cellular function and how its function was related to HL. Recently, a novel mutation in DFNA5 has been identified in a Korean family, totaling five families with DFNA5 HL. 2 These families all have different genomic DFNA5 mutations, but in each case the DFNA5 mRNA transcript skips exon 8, resulting in a frameshift and a premature truncation of the protein. [1][2][3][4][5] These findings have led to the hypothesis that DFNA5-associated HL is attributable to a highly specific gain-of-function mutation, in which skipping of one exon causes disease while mutations in other parts of this gene may not result in HL at all. Further experimental evidence for this hypothesis was provided by the finding that transfection of mutant DFNA5 causes cell death in both yeast 6 and mammalian 7 cells and by the discovery of a new DFNA5 mutation. 8 The latter mutation truncated the protein in the fifth exon, but did not segregate with HL and was present in family members with normal hearing. The hypothesis was further corroborated by a mouse that lacked the Dfna5 protein. This knockout (KO) mouse did not display any HL and, as a consequence, was not a suitable animal model to study DFNA5-associated HL. 9 To date, little information is available on the physiological function of DFNA5. However, since its identification, the small num...

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Section: Discussionmentioning

confidence: 99%

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

et al. 2011

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“…Recent study provides evidence for cell death by an apoptotic mechanism in animal models of ototoxicity associated with abnormal expression of some proteases [34,35]. It is well known that caspase-3 is situated at a key junction in the process, mediating apoptotic cascade from the intrinsic and extrinsic activation pathways [36][37][38]. Once activated, it acts on several targets, each of which Fig.…”

Section: Discussionmentioning

confidence: 99%

Salicylate Initiates Apoptosis in the Spiral Ganglion Neuron of Guinea Pig Cochlea by Activating Caspase-3

et al. 2011

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Salicylate-induced ototoxicity leading to sensorineural hearing loss (SNHL) and tinnitus is well documented. However, the exact mechanisms are poorly defined. Caspase-3 is a member of the class of effector caspases and has been activated in nearly every model of apoptosis. To examine its role in salicylate-induced injury, we subjected guinea pigs to treatment with a specific inhibitor zDEVD-FMK via the round window niche (RWN) followed by a systemic injection of salicylate at a dose of 200 mg · kg(-1) · d(-1) i.p. for 10 consecutive days. For those animals administered with salicylate, immunohistochemical studies revealed that caspase-3 was activated in the spiral ganglion neurons (SGNs) and method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) to identify neuronal apoptosis showed that fragmented nuclei were distributed in Rosenthal's canal. Topical administration of the zDEVD-FMK at a concentration of 500 mM blocked caspase-3 activation and had an effect in reducing the number of TUNEL-positive auditory neurons. In contrast, the inhibitor at a concentration of 125 or 250 mM caused no variation in the expression of activated caspase-3, or in the ratio of TUNEL-positive neurons. These results indicate that caspase-3 is a crucial mediator of apoptosis induced by salicylate in the primary auditory neuron in vivo, and suggest that the specific inhibitor at a relatively high concentration may be therapeutically beneficial in salicylate-induced apoptosis.

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“…A computer-aided evoked potential system was used to test the mice's ABR thresholds as previously described [9]. Under anesthesia, the mice received click, 8-kHz, and 16-kHz pure-tone burst stimuli into their right ears, which were delivered in a sound-isolated and electrically shielded booth (Acoustic Systems, Austin, Tex., USA) via a Beyer earphone.…”

Section: Methodsmentioning

confidence: 99%

Autologous Meatal Skin Graft Implantation and Intratympanic Injection of <b><i>Pseudomonas aeruginosa</i></b>: A New Experimental Mouse Model of Acquired Middle Ear Cholesteatoma

Chen

et al. 2013

ORL

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Aim: To create an experimental model for the biomedical research of middle ear cholesteatoma. Methods: Cholesteatoma was induced in the right ears of mice. An autologous meatal skin graft was implanted into the middle ear via the tympanic membrane followed by an intratympanic injection of Pseudomonas aeruginosa. Six weeks after surgery, the formation of acquired cholesteatoma was evaluated by macroscopic examination, CT scan, and histological analysis. The expressions of TNF-α, IL-1β, and IL-6 were measured with real-time PCR. Auditory-evoked brain stem response was used for assessing the changes in hearing levels. Results: None of the mice died during the modeling time. By the sixth postoperative week, cholesteatoma had successfully formed in 23 out of 25 mice, which equals a success rate of 92%. A CT scan revealed that the cholesteatoma was eroding the cochlea. Furthermore, histological analysis demonstrated a cystic structure covered by stratified squamous epithelium and keratin desquamation in the lamellae inside the cystic cavity in the bullae. All mice with experimentally induced cholesteatoma showed hearing impairment and an upregulated expression of TNF-α, IL-1β, and IL-6. Conclusion: The present study successfully developed a mouse model of acquired middle ear cholesteatoma, which provides an extremely valuable tool for auditory and biomedical research. The modeling approach is technically easy and has a high success rate.

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Activation of cell death pathways in the inner ear of the aging CBA/J mouse

Cited by 67 publications

References 44 publications

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

Salicylate Initiates Apoptosis in the Spiral Ganglion Neuron of Guinea Pig Cochlea by Activating Caspase-3

Autologous Meatal Skin Graft Implantation and Intratympanic Injection of <b><i>Pseudomonas aeruginosa</i></b>: A New Experimental Mouse Model of Acquired Middle Ear Cholesteatoma

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