Concept: Inner ear
To evaluate the onset of vertigo, hearing loss and tinnitus in Ménière’s disease and the associated endolymphatic hydrops (EH) of the inner ear.
The use of small-interfering RNA (siRNA) has great potential for the development of drugs designed to knock down the expression of damage- or disease-causing genes. However, because of the high molecular weight and negative charge of siRNA, it is restricted from crossing the blood-cochlear barrier, which limits the concentration and size of molecules that are able to gain access to cells of the inner ear. Intratympanic approaches, which deliver siRNA to the middle ear, rely on permeation through the round window for access to the structures of the inner ear. We developed an innovative siRNA delivery recombination protein, TAT double-stranded RNA-binding domains (TAT-DRBDs), which can transfect Cy3-labeled siRNA into cells of the inner ear, including the inner and outer hair cells, crista ampullaris, macula utriculi and macula sacculi, through intact round-window permeation in the chinchilla in vivo, and there were no apparent morphological damages for the time of observation. We also found that Cy3-labeled siRNA could directly enter spiral ganglion neurons and the epithelium of the stria vascularis independently; however, the mechanism is unknown. Therefore, as a non-viral vector, TAT-DRBD is a good candidate for the delivery of double-stranded siRNAs for treating various inner ear ailments and preservation of hearing function.Gene Therapy advance online publication, 10 October 2013; doi:10.1038/gt.2013.49.
Variation is a naturally occurring phenomenon that is observable at all levels of morphology, from anatomical variations of DNA molecules to gross variations between whole organisms. The structure of the otic region is no exception. The present paper documents the broad morphological diversity exhibited by the inner ear region of placental mammals using digital endocasts constructed from high-resolution X-ray computed tomography (CT). Descriptions cover the major placental clades, and linear, angular, and volumetric dimensions are reported.
Fish otoliths, biominerals composed of calcium carbonate with a small amount of organic matrix, are involved in the functioning of the inner ear. Starmaker (Stm) from zebrafish (Danio rerio) was the first protein found to be capable of controlling the formation of otoliths. Recently, a gene was identified encoding the Starmaker-like (Stm-l) protein from medaka (Oryzias latipes), a putative homologue of Stm and human dentine sialophosphoprotein. Although there is no sequence similarity between Stm-l and Stm, Stm-l was suggested to be involved in the biomineralization of otoliths, as had been observed for Stm even before. The molecular properties and functioning of Stm-l as a putative regulatory protein in otolith formation have not been characterized yet. A comprehensive biochemical and biophysical analysis of recombinant Stm-l, along with in silico examinations, indicated that Stm-l exhibits properties of a coil-like intrinsically disordered protein. Stm-l possesses an elongated and pliable structure that is able to adopt a more ordered and rigid conformation under the influence of different factors. An in vitro assay of the biomineralization activity of Stm-l indicated that Stm-l affected the size, shape and number of calcium carbonate crystals. The functional significance of intrinsically disordered properties of Stm-l and the possible role of this protein in controlling the formation of calcium carbonate crystals is discussed.
Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.
The cheetah, Acinonyx jubatus, is the fastest living land mammal. Because of its specialized hunting strategy, this species evolved a series of specialized morphological and functional body features to increase its exceptional predatory performance during high-speed hunting. Using high-resolution X-ray computed micro-tomography (μCT), we provide the first analyses of the size and shape of the vestibular system of the inner ear in cats, an organ essential for maintaining body balance and adapting head posture and gaze direction during movement in most vertebrates. We demonstrate that the vestibular system of modern cheetahs is extremely different in shape and proportions relative to other cats analysed (12 modern and two fossil felid species), including a closely-related fossil cheetah species. These distinctive attributes (i.e., one of the greatest volumes of the vestibular system, dorsal extension of the anterior and posterior semicircular canals) correlate with a greater afferent sensitivity of the inner ear to head motions, facilitating postural and visual stability during high-speed prey pursuit and capture. These features are not present in the fossil cheetah A. pardinensis, that went extinct about 126,000 years ago, demonstrating that the unique and highly specialized inner ear of the sole living species of cheetah likely evolved extremely recently, possibly later than the middle Pleistocene.
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 2 years ago
The dispersal of modern humans from Africa is now well documented with genetic data that track population history, as well as gene flow between populations. Phenetic skeletal data, such as cranial and pelvic morphologies, also exhibit a dispersal-from-Africa signal, which, however, tends to be blurred by the effects of local adaptation and in vivo phenotypic plasticity, and that is often deteriorated by postmortem damage to skeletal remains. These complexities raise the question of which skeletal structures most effectively track neutral population history. The cavity system of the inner ear (the so-called bony labyrinth) is a good candidate structure for such analyses. It is already fully formed by birth, which minimizes postnatal phenotypic plasticity, and it is generally well preserved in archaeological samples. Here we use morphometric data of the bony labyrinth to show that it is a surprisingly good marker of the global dispersal of modern humans from Africa. Labyrinthine morphology tracks genetic distances and geography in accordance with an isolation-by-distance model with dispersal from Africa. Our data further indicate that the neutral-like pattern of variation is compatible with stabilizing selection on labyrinth morphology. Given the increasingly important role of the petrous bone for ancient DNA recovery from archaeological specimens, we encourage researchers to acquire 3D morphological data of the inner ear structures before any invasive sampling. Such data will constitute an important archive of phenotypic variation in present and past populations, and will permit individual-based genotype-phenotype comparisons.
The rapid growth of aquaculture raises questions about the welfare status of mass-produced species. Sagittal otoliths are primary hearing structures in the inner ear of all teleost (bony) fishes and are normally composed of aragonite, though abnormal vaterite replacement is sometimes seen in the wild. We provide the first widespread evaluation of the prevalence of vaterite in otoliths, showing that farmed fish have levels of vaterite replacement over 10 times higher than wild fish, regardless of species. We confirm this observation with extensive sampling of wild and farmed Atlantic salmon in Norway, the world’s largest producer, and verify that vateritic otoliths are common in farmed salmon worldwide. Using a mechanistic model of otolith oscillation in response to sound, we demonstrate that average levels of vaterite replacement result in a 28-50% loss of otolith functionality across most of a salmonid’s known hearing range and throughout its life cycle. The underlying cause(s) of vaterite formation remain unknown, but the prevalence of hearing impairment in farmed fish has important implications for animal welfare, the survival of escapees and their effects on wild populations, and the efficacy of restocking programs based on captive-bred fish.
Because there are currently no biological treatments for hearing loss, we sought to advance gene therapy approaches to treat genetic deafness. We focused on Usher syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and studied a knock-in mouse model, Ush1c c.216G>A, for Usher syndrome type IC (USH1C). As restoration of complex auditory and balance function is likely to require gene delivery systems that target auditory and vestibular sensory cells with high efficiency, we delivered wild-type Ush1c into the inner ear of Ush1c c.216G>A mice using a synthetic adeno-associated viral vector, Anc80L65, shown to transduce 80-90% of sensory hair cells. We demonstrate recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders.
High morphological variation of vestibular system accompanies slow and infrequent locomotion in three-toed sloths.
- Proceedings. Biological sciences / The Royal Society
- Published over 7 years ago
The semicircular canals (SCs), part of the vestibular apparatus of the inner ear, are directly involved in the detection of angular motion of the head for maintaining balance, and exhibit adaptive patterns for locomotor behaviour. Consequently, they are generally believed to show low levels of intraspecific morphological variation, but few studies have investigated this assumption. On the basis of high-resolution computed tomography, we present here, to our knowledge, the first comprehensive study of the pattern of variation of the inner ear with a focus on Xenarthra. Our study demonstrates that extant three-toed sloths show a high level of morphological variation of the bony labyrinth of the inner ear. Especially, the variation in shape, relative size and angles of their SCs greatly differ from those of other, faster-moving taxa within Xenarthra and Placentalia in general. The unique pattern of variation in three-toed sloths suggests that a release of selection and/or constraints on their organ of balance is associated with the observed wide range of phenotypes. This release is coincident with their slow and infrequent locomotion and may be related, among other possible factors, to a reduced functional demand for a precise sensitivity to movement.