Progression of inner ear pathology in Ames waltzer mice and the role of protocadherin 15 in hair cell development.

Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-9035, USA.
Journal of the Association for Research in Otolaryngology (Impact Factor: 2.55). 07/2006; 7(2):83-94. DOI: 10.1007/s10162-005-0024-5
Source: PubMed

ABSTRACT The Ames waltzer (av) mouse mutant exhibits auditory and vestibular abnormalities resulting from mutation of protocadherin 15 (Pcdh15). Ames waltzer has been identified as an animal model for inner ear pathology associated with Usher syndrome type 1F. Studies correlating anatomical phenotype with severity of genetic defect in various av alleles are providing better understanding of the role played by Pcdh15 in inner ear development and of sensorineural abnormalities associated with alterations in Pcdh15 protein structure as a result of gene mutation. In this work we present new findings on inner ear pathology in four alleles of av mice with differing mutations of Pcdh15 as well as varying alterations in inner ear morphology. Two alleles with in-frame deletion mutations (Pcdh15 (av-J) and Pcdh15 (av-2J)) and two presumptive functional null alleles (Pcdh15 (av-3J) and Pcdh15 (av-Tg)) were studied. Light and electron microscopic observations demonstrated that the severity of cochlear and vestibular pathology in these animals correlates positively with the extent of mutation in Pcdh15 from embryonic day 18 (E18) up to 12 months. Electron microscopic analysis of immature ears indicated early abnormalities in the arrangement of stereocilia and the inner and outer hair cell cuticular plates, stereocilia rootlets, and the actin meshwork within the cuticular plate. In severe cases, displacement of the kinocilium and alterations in the shape of the cuticular plate was also observed. Mice harboring in-frame deletion mutations showed less disorganization of stereocilia and cuticular plates in the organ of Corti than the presumptive functional null alleles at P0-P10. A slower progression of pathology was also seen via light microscopy in older animals with in-frame deletions, compared to the presumptive functional null mutations. In summary, our results demonstrate that mutation in Pcdh15 affects the initial formation of stereocilia bundles with associated changes in the actin meshwork within the cuticular plate; these effects are more pronounced in the presumed null mutation compared to mutations that only affect the extracellular domain. The positive correlation of severity of effects with extent of mutation can be seen well into adulthood.

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Available from: Karen S Pawlowski, Aug 03, 2015
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    • "In cases where the insult is severe or a prolonged period of time has passed since the insult, the supporting cells may degenerate as well and form or are replaced by a flat layer of polymorphic cuboidal cells, which we refer to as the " flat epithelium " (Fig. 1C) (Kim et al., 2007). The flat epithelium can be observed frequently as the outcome of severe hearing loss caused by various etiologies including hereditary deafness (Pawlowski et al., 2006), aminoglycoside insult in guinea pigs (Izumikawa et al., 2008; Shibata et al., 2010), and in humans with prolonged history of deafness (Nadol et al., 2006). This highly degenerated condition of sensory epithelium that remains in the deaf ears will likely be the substrate to first receive any of the future therapies. "
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    ABSTRACT: Following the onset of sensorineural hearing loss, degeneration of mechanosensitive hair cells and spiral ganglion cells (SGCs) in humans and animals occurs to variable degrees, with a trend for greater neural degeneration with greater duration of deafness. Emergence of the cochlear implant prosthesis has provided much needed aid to many hearing impaired patients and has become a well-recognized therapy worldwide. However, ongoing peripheral nerve fiber regression and subsequent degeneration of SGC bodies can reduce the neural targets of cochlear implant stimulation and diminish its function. There is increasing interest in bio-engineering approaches that aim to enhance cochlear implant efficacy by preventing SGC body degeneration and/or regenerating peripheral nerve fibers into the deaf sensory epithelium. We review the advancements in maintaining and regenerating nerves in damaged animal cochleae, with an emphasis on the therapeutic capacity of neurotrophic factors delivered to the inner ear after an insult. Additionally, we summarize the histological process of neuronal degeneration in the inner ear and describe different animal models that have been employed to study this mechanism. Research on enhancing the biological infrastructure of the deafened cochlea in order to improve cochlear implant efficacy is of immediate clinical importance.
    Hearing research 05/2011; 281(1-2):56-64. DOI:10.1016/j.heares.2011.04.019 · 2.85 Impact Factor
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    • "DEVELOPMENT Palma et al., 2001; Wilson et al., 2001; Pawlowski et al., 2006; Senften et al., 2006; Lefevre et al., 2008 "
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    ABSTRACT: Protocadherin 15 (PCDH15) is expressed in hair cells of the inner ear and in photoreceptors of the retina. Mutations in PCDH15 cause Usher Syndrome (deaf-blindness) and recessive deafness. In developing hair cells, PCDH15 localizes to extracellular linkages that connect the stereocilia and kinocilium into a bundle and regulate its morphogenesis. In mature hair cells, PCDH15 is a component of tip links, which gate mechanotransduction channels. PCDH15 is expressed in several isoforms differing in their cytoplasmic domains, suggesting that alternative splicing regulates PCDH15 function in hair cells. To test this model, we generated three mouse lines, each of which lacks one out of three prominent PCDH15 isoforms (CD1, CD2 and CD3). Surprisingly, mice lacking PCDH15-CD1 and PCDH15-CD3 form normal hair bundles and tip links and maintain hearing function. Tip links are also present in mice lacking PCDH15-CD2. However, PCDH15-CD2-deficient mice are deaf, lack kinociliary links and have abnormally polarized hair bundles. Planar cell polarity (PCP) proteins are distributed normally in the sensory epithelia of the mutants, suggesting that PCDH15-CD2 acts downstream of PCP components to control polarity. Despite the absence of kinociliary links, vestibular function is surprisingly intact in the PCDH15-CD2 mutants. Our findings reveal an essential role for PCDH15-CD2 in the formation of kinociliary links and hair bundle polarization, and show that several PCDH15 isoforms can function redundantly at tip links.
    Development 04/2011; 138(8):1607-17. DOI:10.1242/dev.060061 · 6.27 Impact Factor
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    • "We refer to this severely lesioned tissue as the flat epithelium (FE). Presence of the FE has been observed after a long period of deafness following kanamycin treatment (Sugawara, et al., 2005), after genetic hearing loss (Pawlowski, et al., 2006) and other etiologies for animal deafness, and in human temporal bone studies of patients with congenital diseases, including some who also received a cochlear implant (Nadol, 1997, Nadol and Eddington, 2006, Teufert, et al., 2006). Patients with profound deafness and FE are among those who receive cochlear implants, and may be the first candidate population for future stem cell therapies. "
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    ABSTRACT: Sensory organs typically use receptor cells and afferent neurons to transduce environmental signals and transmit them to the CNS. When sensory cells are lost, nerves often regress from the sensory area. Therapeutic and regenerative approaches would benefit from the presence of nerve fibers in the tissue. In the hearing system, retraction of afferent innervation may accompany the degeneration of auditory hair cells that is associated with permanent hearing loss. The only therapy currently available for cases with severe or complete loss of hair cells is the cochlear implant auditory prosthesis. To enhance the therapeutic benefits of a cochlear implant, it is necessary to attract nerve fibers back into the cochlear epithelium. Here we show that forced expression of the neurotrophin gene BDNF in epithelial or mesothelial cells that remain in the deaf ear induces robust regrowth of nerve fibers towards the cells that secrete the neurotrophin, and results in re-innervation of the sensory area. The process of neurotrophin-induced neuronal regeneration is accompanied by significant preservation of the spiral ganglion cells. The ability to regrow nerve fibers into the basilar membrane area and protect the auditory nerve will enhance performance of cochlear implants and augment future cell replacement therapies such as stem cell implantation or induced transdifferentiation. This model also provides a general experimental stage for drawing nerve fibers into a tissue devoid of neurons, and studying the interaction between the nerve fibers and the tissue.
    Experimental Neurology 06/2010; 223(2):464-72. DOI:10.1016/j.expneurol.2010.01.011 · 4.62 Impact Factor
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