Characteristics of stria vascularis melanocytes of viable dominantspotting (WvWv) mouse mutants

doi:10.1016/0378-5955(92)90164-I

Hearing Research

Volume 64, Issue 1, December 1992, Pages 6-20

https://doi.org/10.1016/0378-5955(92)90164-I Get rights and content

Abstract

The W^v mutation lies in the kinse domain of the proto-oncogene c-kit which is expressed in a variety of cells including neural crest derived melanoblasts The mutation results in the abnormal migration, proliferation, survival and/or differentiation of melanoblasts. Viable Dominant Spotting ( $W^{v} W^{v}$ ) mouse mutants have a white coat due to the absence of melanocytes. The majority of these animals have no melanocytes within the stria vasculans and no endocochlear potential (EP). A proportion of homozygous mutants partially escape the effects of the mutation 47 2% of pinnae and 21% of vestibular regions were pigmented and 10 8% of ears had an EP. All ears with an EP that were available for histology had some pigmentation of the stria. There was no obvious correlation between external and internal spotting in $W^{v} W^{v}$ mice, and asymmetrical pigmentation of the ears was common. Both light and dark intermediate cells (which are derived from melanocytes) were present in the middle and/or basal turns of these cochlear ducts and they appeared to function normally in enabling the stria to produce an EP (although the EP was usually lower than normal). This suggests that the c-kit gene product is needed only during development of the stria, and not for mature melanocyte function because the melanocytes present in the mutant strias were carrying the mutant version of the c-kit gene. Melanocytes were similar in appearance in controls and mutants, except that fewer melanin granules were observed in the strias of $W^{v} W^{v}$ mice. The observations that strial melanocytes with very few melanin granules in $W^{v} W^{v}$ mutants are able to support EP production, together with previous observations that albino animals with strial melanocytes but no melanin have a normal EP, suggest that melanocytes but not melanin are essential for normal strial function.

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The primary cause of Norrie Disease is the strial avascularity associated with an Ndp gene defect (Rehm et al., 2002). Dominant white spotting [W/W(v) and W(v)/W(v)] mice are well-known mutants with profound sensorineural hearing loss (Cable et al., 1992; Fujimura et al., 2005). The mutants lack strial intermediate cells.
The blood-labyrinth barrier (BLB) in the stria vascularis is a highly specialized capillary network that controls exchanges between blood and the intrastitial space in the cochlea. The barrier shields the inner ear from blood-born toxic substances and selectively passes ions, fluids, and nutrients to the cochlea, playing an essential role in the maintenance of cochlear homeostasis. Anatomically, the BLB is comprised of endothelial cells (ECs) in the strial microvasculature, elaborated tight and adherens junctions, pericytes (PCs), basement membrane (BM), and perivascular resident macrophage-like melanocytes (PVM/Ms), which together form a complex “cochlear-vascular unit” in the stria vascularis. Physical interactions between the ECs, PCs, and PVM/Ms, as well as signaling between the cells, is critical for controlling vascular permeability and providing a proper environment for hearing function. Breakdown of normal interactions between components of the BLB is seen in a wide range of pathological conditions, including genetic defects and conditions engendered by inflammation, loud sound trauma, and ageing. In this review, we will discuss prevailing views of the structure and function of the strial cochlear-vascular unit (also referred to as the “intrastrial fluid-blood barrier”). We will also discuss the disrupted homeostasis seen in a variety of hearing disorders. Therapeutic targeting of the strial barrier may offer opportunities for improvement of hearing health and amelioration of auditory disorders.
This article is part of a Special Issue entitled <Annual Reviews 2016>.
Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2
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This indicates that KITLG mutations are not a frequent cause of bilateral symmetric sensorineural HI. KITLG-KIT signaling plays a role in proliferation, migration from the neural crest, and survival and differentiation of hematopoietic precursor cells, primordial germ cells, and melanoblasts.25–28,39 In mice, severe mutations in Kitl (Sl locus) and Kit (W locus) are embryonic lethal when homozygous, but viable when compound heterozygous with less severe defects, as are semi-dominant mutations.40–42
Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.
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In the vertebrate head, the peripheral components of the sensory nervous system are derived from two embryonic cell populations, the neural crest and cranial sensory placodes. Both arise in close proximity to each other at the border of the neural plate: neural crest precursors abut the future central nervous system, while placodes originate in a common preplacodal region slightly more lateral. During head morphogenesis, complex events organise these precursors into functional sensory structures, raising the question of how their development is coordinated. Here we review the evidence that neural crest and placode cells remain in close proximity throughout their development and interact repeatedly in a reciprocal manner. We also review recent controversies about the relative contribution of the neural crest and placodes to the otic and olfactory systems. We propose that a sequence of mutual interactions between the neural crest and placodes drives the coordinated morphogenesis that generates functional sensory systems within the head.
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The ear is the vertebrate sense organ of hearing and balance. Neural crest cells (NCC), notable for varied contributions to other parts of the head and body, contribute multiple tissues to the ear. In higher vertebrates the ear is composed of three distinct compartments, the inner, middle, and outer ear, each requiring developmental contribution from NCC. Within the inner ear, NCC are progenitors of Schwann cells of the cochleovestibular nerve and melanocytes of the cochlea. For the middle ear and outer ear, NCC produce bone and cartilage and, by developmental remodeling, the air-filled cavities essential for hearing. Abnormalities of NCC cause hearing loss, sensorineural in the case of inner ear NCC, or conductive in the case of middle and outer ear NCC. Middle ear, outer ear, and jaw elements of different vertebrates exhibit key evolutionary variation, a result of alterations in derivatives of first and second pharyngeal arch NCC.
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Each component of the human ear performs a specific function in hearing. The actual process of sound transduction takes place in the auditory portion of the inner ear, the fluid-filled cochlea. In the cochlea, the sensitivity and efficiency of sensory apparatus to convert mechanical energy into neural activity, largely depends on the fluidic and ionic environment. In the lateral wall of cochlea, the secretory epithelium stria vascularis plays an important role in the maintenance of fluidic and ionic homeostasis. A variety of gene mutations disturbs the cochlear homeostasis and subsequently leads to hearing impairment. The review covers several aspects of cochlear homeostasis, from cochlear fluid and the functional role of stria vascularis, cochlear K⁺ recycling and its molecular substrates to genetic deafness with abnormal cochlear homeostasis.

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Characteristics of stria vascularis melanocytes of viable dominantspotting (WvWv) mouse mutants

Abstract

Cell

Cell

Cell

Dev Biol

Dev Biol

Dev Biol

Hear Res

Adv Genetics

Arch Biochem Biophys

Hear Res

Cell

The effects of ethacrynic acid upon the cochlear endolymph and stria vascularis

Acta Otolaryngol

The endocochlear potential in the shaker-1 (sh-1/sh-1) mouse

Acta Otolaryngol

Identification of two types of melanocyte within the stria vascularis of the mouse inner ear

Pigment Cell Res

Endocochlear potential generation is associated with intracellular communication in the stria vascularis structural analysis in the Viable Dominant Spotting mouse

Cell and Tissue Res

The proto-oncogene c-kit encoding a transmembrane tyrosme kinase receptor maps to the mouse W locus

Nature

Contributions of placodal and neural crest cells to avian cranial peripheral ganglia

Am J Anat

The relationship between abnormalities of pigmentation and of the inner ear

The origin of the acoustic ganglion and effects of the gene dominant spotting (Wv) in the mouse

J Embryol Exp Morph

Some otological differences between pigmented and albino-type guinea pigs

Arch Oto-Rhino-Laryngol

Distortion product otoacoustic emissions in hearing-impaired mutant mice

J Acoust Soc Am

Characteristics of stria vascularis melanocytes of viable dominantspotting ( $W^{v} W^{v}$ ) mouse mutants

The origin of the acoustic ganglion and effects of the gene dominant spotting (W^v) in the mouse