Deafness and Cochlear Fibrocyte Alterations in Mice Deficient for the Inner Ear Protein Otospiralin

Abstract

In the cochlea, the mammalian auditory organ, fibrocytes of the mesenchymal nonsensory regions play important roles in cochlear physiology, including the maintenance of ionic and hydric components in the endolymph. Occurrence of human deafness in fibrocyte alterations underlines their critical roles in auditory function. We recently described a novel gene, Otos, which encodes otospiralin, a small protein of unknown function that is produced by the fibrocytes of the cochlea and vestibule. We now have generated mice with deletion of Otos and found that they show moderate deafness, with no frequency predominance. Histopathology revealed a degeneration of type II and IV fibrocytes, while hair cells and stria vascularis appeared normal. Together, these findings suggest that impairment of fibrocytes caused by the loss in otospiralin leads to abnormal cochlear physiology and auditory function. This moderate dysfunction may predispose to age-related hearing loss.Within the cochlea, the mammalian auditory organ, mesenchymal nonsensory regions (i.e., the spiral limbus proximal to the cochlear axis and the spiral ligament forming the lateral wall of the cochlea) contain fibrocytes that play important roles in cochlear physiology. In the spiral ligament, these fibrocytes form distinct groups according to their location, morphological appearance, and marker expression, which suggest their functional specialization (26). Thus, the circumferentially oriented type III fibrocytes lining the otic capsule and the spindleshaped type IV fibrocytes lateral to the basilar membrane package the cochlear content and buffer mechanical constraints generated by sound vibrations (8). The type I fibrocytes (behind the stria vascularis), tightly packed with collagen bundles, shape the curvature of the lateral wall. Type II fibrocytes (below the stria vascularis) and type V fibrocytes (above the stria vascularis) are rich in mitochondria and form many interdigitating processes, indicating high metabolic and exchange activities. Type I, II, and V fibrocytes and basal and intermediate cells of the stria vascularis are all interconnected with gap junctions (10). This gap-junctioned network is postulated to be involved in ion and water circulation, including potassium recycling (34). Potassium is indeed central to the cochlear physiology, since it is the charge-carrying ion for the sensory transduction. It is secreted by the marginal cells of the stria vascularis to maintain a very high concentration (150 mM) in the endolymph, the extracellular fluid bathing hair cell stereocilia. Recycling of potassium though the fibrocyte network is one of several processes that provide potassium to intermediate cells of the stria vascularis (28, 34). This permanent flux of potassium cycling in the cochlea generates the so-called "endocochlear potential " (ϩ85 mV), which gives the main driving force for potassium entry into the sensory hair cell.Progress in the functional characterization of the cochlear fibrocytes has been made with the discovery of proteins exp...

Deafness in mice lacking the T-box transcription factor Tbx18 in otic fibrocytes

“…fibrocytes type II and IV are degenerated (Delprat et al, 2005). Similar to Pou3f4, the precise role of Otos in fibrocyte differentiation is unknown.…”

“…The importance of fibrocyte integrity in this process has become apparent by pathological changes caused by inherited disorders or environmental stress. Genetic ablation of certain fibrocyte-expressed genes is known to cause deafness (Minowa et al, 1999;Teubner et al, 2003;Boettger et al, 2003;Delprat et al, 2005), and noise-induced, as well as age-related, hearing deficits are initiated by changes in fibrocyte physiology (Hequembourg and Liberman, 2001;Hirose and Liberman, 2003).…”

Relative Time Course of Degeneration of Different Cochlear Structures in the CD/1 Mouse Model of Accelerated Aging

“…Type I fibrocytes are lateral to the SV, type II lateral to the spiral prominence epithelium, type III along the external edge of SL, type IV in the basilar crest region and type V are supra-strial Schulte 1991, 2002;Nakazawa et al 1995;Suko et al 2000;Weber et al 2001). Fibrocyte degeneration occurs in various mouse strains (Hequembourg and Liberman 2001;Wu and Marcus 2003), in labyrinthitis (Ichimiya et al 1998), otitis media (Ichimiya et al 1999), genetic hearing loss DFN3 (Minowa et al 1999), noise exposure (Hirose and Liberman 2003) and otospiralin knock-outs (Delprat et al 2005).…”

Fibrocytes in the cochlea of the mammalian inner ear: their molecular architecture, physiological properties, and pathological relevance

“…81 In mice, a knockout of the Otos gene-which encodes otospiralin, another extracellular-matrix protein in the ligament-causes hearing loss accompanied by degeneration of the fibrocytes. 82 It is noteworthy that in these animals, the hair cells are preserved. Physiological functions of cochlin and otospiralin remain unclear.…”