The deafness gene<i>dfna5</i>is crucial for<i>ugdh</i>expression and HA production in the developing ear in zebrafish

Busch-Nentwich, Elisabeth M; Söllner, Christian; Roehl, Henry; Nicolson, Teresa

doi:10.1242/dev.00961

Cited by 61 publications

(61 citation statements)

References 42 publications

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“…The latter could be explained by the fact that when apoptotic pathways are downregulated, DNA repair mechanisms need to be upregulated to maintain viable conditions. Interestingly, genes involved in cartilage maintenance were also upregulated in Dfna5 KO mice, linking our findings to those obtained by Busch-Nentwich et al 22 They found that zebrafish injected with Dfna5 morpholino's displayed an absent expression of Ugdh (UDPglucose dehydrogenase), leading to reduced production of hyaluronic acid, resulting in impaired facial cartilage differentiation. As Dfna5 KO mice do not display this phenotype, it is possible that the gene sets involved in cartilage development provide compensatory mechanisms resulting in the lack of phenotype in these mice.…”

Section: Discussionsupporting

confidence: 89%

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: Discussionsupporting

confidence: 89%

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

et al. 2011

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“…3F,G). Expression of the semicircular canal tissue markers ugdh1 (Busch-Nentwich et al, 2004) and dacha (Hammond et al, 2002) is, however, normal in the epithelial projections that are present (data not shown). The otoliths remain very small and sit close to one another in the mutant (Fig.…”

Section: Otic Vesicle Morphology Is Abnormal In Sox10 Mutantsmentioning

confidence: 90%

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle

Dutton

Abbas

Spencer

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARYIn humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.

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“…The early development of the zebrafish inner ear is similar to that of other vertebrates (Bang et al, 2001;Whitfield et al, 2002;Riley and Phillips, 2003) and its sensory hair cells are homologous to those found in mammals (Coffin et al, 2004). Over 50 genes are known to impact the zebrafish auditory inner ear and/or vestibular system Whitfield et al, 1996;Whitfield et al, 2002;Riley and Phillips, 2003;Starr et al, 2004;Nicolson, 2005) and many of these genes are conserved and affect the inner ear development and function in other vertebrates, including humans (Nicolson et al, 1998;Moorman et al, 1999;Riley and Moorman, 2000;Busch-Nentwich et al, 2004;Kappler et al, 2004;Kozlowski et al, 2005). However, unlike mammals, zebrafish develop from eggs ex utero and are transparent during the first few weeks of life.…”

Section: Introductionmentioning

confidence: 95%

Auditory sensitivity of larval zebrafish (Danio rerio) measured using a behavioral prepulse inhibition assay

Bhandiwad

Zeddies²,

Raible

et al. 2013

Journal of Experimental Biology

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SUMMARYZebrafish (Danio rerio) have become a valuable model for investigating the molecular genetics and development of the inner ear in vertebrates. In this study, we employed a prepulse inhibition (PPI) paradigm to assess hearing in larval wild-type (AB) zebrafish during early development at 5-6days post-fertilization (d.p.f.). We measured the PPI of the acoustic startle response in zebrafish using a 1-dimensional shaker that simulated the particle motion component of sound along the fish's dorsoventral axis. The thresholds to startle-inducing stimuli were determined in 5-6d.p.f. zebrafish, and their hearing sensitivity was then characterized using the thresholds of prepulse tone stimuli (90-1200Hz) that inhibited the acoustic startle response to a reliable startle stimulus (820Hz at 20dB re. 1ms). Hearing thresholds were defined as the minimum prepulse tone level required to significantly reduce the startle response probability compared with the baseline (no-prepulse) condition. Larval zebrafish showed greatest auditory sensitivity from 90 to 310Hz with corresponding mean thresholds of −19 to −10dB re. 1ms -2 , respectively. Hearing thresholds of prepulse tones were considerably lower than previously predicted by startle response assays. The PPI assay was also used to investigate the relative contribution of the lateral line to the detection of acoustic stimuli. After aminoglycoside-induced neuromast hair-cell ablation, we found no difference in PPI thresholds between treated and control fish. We propose that this PPI assay can be used to screen for novel zebrafish hearing mutants and to investigate the ontogeny of hearing in zebrafish and other fishes.

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The deafness genedfna5is crucial forugdhexpression and HA production in the developing ear in zebrafish

Cited by 61 publications

References 42 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

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle

Auditory sensitivity of larval zebrafish (Danio rerio) measured using a behavioral prepulse inhibition assay

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