Neuroepithelial defects of the inner ear in a new allele of the mouse mutation Ames waltzer

Alagramam, Kumar N.; Zahorsky-Reeves, Joanne; Wright, Charles G.; Pawlowski, Karen S.; Erway, Lawrence C.; Stubbs, Lisa; Woychik, Richard P.

doi:10.1016/s0378-5955(00)00152-0

Cited by 44 publications

(35 citation statements)

References 20 publications

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“…The behavior of rats homozygous for the kci mutation is very similar to those described previously in mouse Pcdh15-mutant alleles [4,5,8,17,18]. The mutation in the kci allele is a nonsense mutation (c. 2911 C>T, p. Arg971X) and is predicted to result in truncated PCDH15 protein at the 9th domain of extracellular cadherin domains.…”

Section: Discussionsupporting

confidence: 76%

“…The Pcdh15 kci allele is a functional null, because the mutation introduces a stop codon, and it is included in the repertoire of rodent Pcdh15 mutant alleles. Mature KCI rats show constant circling behavior and histological defects in both cochlear and vestibular hair cells, which are comparable with those observed in mouse Pcdh15-null alleles such as av Tg , av 5J , or av Jfb [4,8,17].…”

Section: Discussionsupporting

confidence: 72%

“…Genetic analysis of mouse Ames waltzer (av) mutation, which causes deafness and vestibular dysfunction associated with degeneration of the inner ear neuroepithelia, identified protocadherin 15 (Pcdh15) as the gene responsible for hearing impairment [5]. Several [4,5,8,17,18]. Extensive analyses of these av mutants show that mutation in Pcdh15 affects hair bundle morphogenesis and polarity [8,12,17] and mechanotransduction [7].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

et al. 2009

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Protocadherin-15 (Pcdh15) plays important roles in the morphogenesis and cohesion of stereocilia bundles and in the maintenance of retinal photoreceptor cells. In humans, mutations in PCDH15 cause Usher syndrome type 1F (USH1F) and non-syndromic deafness DFNB23. In mice, repertories of Pcdh15 mutant alleles have been described as Ames waltzer mutations. For further understanding of Pcdh15 function in vivo and to develop better clinical treatment for the disabling symptoms of USH1F and DFNB23 patients, animal models suitable for clinical as well as pharmacological studies are required. Here we report the characterization of a Pcdh15 mutant allele, Kyoto circling, (Pcdh15 kci ) in the rat. Rats homozygous for Pcdh15 kci display circling and abnormal swimming behaviors along with the lack of an auditory-evoked brainstem response at the highest intensities of acoustic stimulation. Positional cloning analysis revealed a nonsense mutation (c. 2911C>T, p. Arg971X) in the Pcdh15 gene, which is predicted to result in the truncation of the PCDH15 protein at the 9th domain of cytoplasmic cadherin domains. Histological study revealed severe defects in cochlear hair cell stereocilia, collapse of the organ of Corti, and marked reduction of ganglion cells in adult Pcdh15 kci mutants. Severe reduction of sensory hair cells was also found in the saccular macula. Since the rat is more advantageous for clinical and pharmacological studies than the mouse, the KCI rat strain may be a better disease model for Pcdh15-deficit USH1F and DFNB23.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

et al. 2009

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“…This finding has been described in human temporal bone specimens of patients with MD (Nadol, 1990;Nadol et al, 1987Nadol et al, ,1995. This feature is unlike what is observed in other mouse models of sensorineural deafness, where loss of spiral ganglion cells is secondary to hair cell loss (Alagramam et al, 2000). Further, in Phex Hyp-Duk /Y mice, degeneration of neuronal cells in the cochlea shows an apex to base progression.…”

Section: Discussionmentioning

confidence: 45%

A mouse model with postnatal endolymphatic hydrops and hearing loss

et al. 2008

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Endolymphatic hydrops (ELH), hearing loss and neuronal degeneration occur together in a variety of clinically significant disorders, including Meniere's disease (MD). However, the sequence of these pathological changes and their relationship to each other are not well understood. In this regard, an animal model that spontaneously develops these features postnatally would be useful for research purposes. A search for such a model led us to the Phex Hyp-Duk mouse, a mutant allele of the Phex gene causing X-linked hypophosphatemic rickets. The hemizygous male (Phex Hyp-Duk /Y) was previously reported to exhibit various abnormalities during adulthood, including thickening of bone, ELH and hearing loss. The reported inner-ear phenotype was suggestive of progressive pathology and spontaneous development of ELH postnatally, but not conclusive. The main focuses of this report are to further characterize the inner ear phenotype in Phex Hyp-Duk /Y mice and to test the hypotheses that (a) the Phex Hyp-Duk /Y mouse develops ELH and hearing loss postnatally, and (b) the development of ELH in the Phex Hyp-Duk /Y mouse is associated with obstruction of the endolymphatic duct (ED) due to thickening of the surrounding bone. Auditory brainstem response (ABR) recordings at various times points and histological analysis of representative temporal bones reveal that Phex Hyp-Duk /Y mice typically develop adult onset, asymmetric, progressive hearing loss closely followed by the onset of ELH. ABR and histological data show that functional degeneration precedes structural degeneration. The major degenerative correlate of hearing loss and ELH in the mutants is the primary loss of spiral ganglion cells. Further, Phex Hyp-Duk /Y mice develop ELH without evidence of ED obstruction, supporting the idea that ELH can be induced by a mechanism other than the blockade of longitudinal flow of endolymphatic fluid, and occlusion of ED is not a prerequisite for the development of ELH in patients.

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“…Furthermore, in vitro data indicate that Myo7A also interacts with protocadherin 15 (PCDH15) (Senften et al, 2006), another USH1-associated protein that appears to interact heterophilically with CDH23, thereby connecting two neighboring stereocilia through a tip link (Kazmierczak et al, 2007). Similar to Myo7A mutants, Pcdh15 mutants show a severe disorganization of stereocilia bundles (Alagramam et al, 2000;Alagramam et al, 2001;Raphael et al, 2001;Seiler et al, 2005;Lefèvre et al, 2008). A recent study suggests that Myosin VIIB, a close relative of Myo7A, interacts with protocadherin-24 and mucin-like protocadherin, two heterophilically interacting cadherins that are involved in the proper formation of the brush border in enterocytes (Crawley et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Myosin VIIA regulates microvillus morphogenesis and interacts with cadherin Cad99C in Drosophila oogenesis

Glowinski

Liu

Chen

et al. 2014

Journal of Cell Science

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BSTRACTMicrovilli and related actin-based protrusions permit multiple interactions between cells and their environment. How the shape, length and arrangement of microvilli are determined remains largely unclear. To address this issue and explore the cooperation of the two main components of a microvillus, the central F-actin bundle and the enveloping plasma membrane, we investigated the expression and function of Myosin VIIA (Myo7A), which is encoded by crinkled (ck), and its interaction with cadherin Cad99C in the microvilli of the Drosophila follicular epithelium. Myo7A is present in the microvilli and terminal web of follicle cells, and associates with several other F-actin-rich structures in the ovary. Loss of Myo7A caused brush border defects and a reduction in the amount of the microvillus regulator Cad99C. We show that Myo7A and Cad99C form a molecular complex and that the cytoplasmic tail of Cad99C recruits Myo7A to microvilli. Our data indicate that Myo7A regulates the structure and spacing of microvilli, and interacts with Cad99C in vivo. A comparison of the mutant phenotypes suggests that Myo7A and Cad99C have co-dependent and independent functions in microvilli.

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Neuroepithelial defects of the inner ear in a new allele of the mouse mutation Ames waltzer

Cited by 44 publications

References 20 publications

Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

A mouse model with postnatal endolymphatic hydrops and hearing loss

Myosin VIIA regulates microvillus morphogenesis and interacts with cadherin Cad99C in Drosophila oogenesis

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