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Rev Laryngol Otol Rhinol (Bord). 2008;129(1):3-9. Review.
Rev Laryngol Otol Rhinol (Bord). 2008;129(1):3-9. Review.
PMID: 18777763 [
PMID: 18777763 [
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==Vestibular Development==
1. Pendred Syndrome/DFNB4.
Smith RJH, Van Camp G.
In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet].
Seattle (WA): University of Washington, Seattle; 1993-.
1998 Sep 28.
Disease characteristics. Pendred syndrome and DFNB4 comprise a phenotypic
spectrum of hearing loss with or without other findings. Pendred syndrome is
characterized by severe-to-profound bilateral sensorineural hearing impairment
that is usually congenital and non-progressive, vestibular dysfunction, temporal
bone abnormalities, and development of euthyroid goiter in late childhood to
early adulthood. Variability of findings is considerable, even within the same
family. DFNB4 is characterized by nonsyndromic sensorineural hearing impairment,
vestibular dysfunction, and temporal bone abnormalities. Thyroid defects are not
seen in DFNB4. Diagnosis/testing. Pendred syndrome and DFNB4 are diagnosed
clinically in individuals with (1) hearing impairment that is usually congenital
and often severe to profound, although mild-to-moderate progressive hearing
impairment also occurs; and (2) bilateral dilation of the vestibular aqueduct
(DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear
hypoplasia (the presence of both DVA and cochlear hypoplasia is known as Mondini
malformation or dysplasia). In addition, individuals with Pendred syndrome have
either an abnormal perchlorate discharge test or goiter (when no other etiology
of the goiter is evident and perchlorate washout cannot be performed). The only
two genes known to be associated with Pendred syndrome/DFNB4 are SLC26A4 (~50% of
affected individuals) and FOXI1 (~1% of affected individuals, suggesting further
genetic heterogeneity). Sequence analysis identifies disease-causing mutations in
approximately 50% of affected individuals from multiplex families and 20% of
individuals from simplex families; such testing is clinically available. FOXI1
testing is available on a research basis only. Management.
Treatment of manifestations: hearing habituation, hearing aids, and educational
programs designed for the hearing impaired; consideration of cochlear
implantation in individuals with severe-to-profound deafness. Standard treatment
of abnormal thyroid function. Surveillance: semiannual or annual assessment of
hearing and endocrine function. Repeat audiometry initially every three to six
months if hearing loss is progressive. Agents/circumstances to avoid:
weightlifting and contact sports. Genetic counseling. Pendred syndrome/DFNB4 is
inherited in an autosomal recessive manner. At conception, each sib of an
affected individual has a 25% chance of being affected, a 50% chance of being an
asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Carrier testing for at-risk family members and prenatal testing for at-risk
pregnancies are possible when the family-specific mutations are known.
PMID: 20301640 [PubMed]
2. Dev Dyn. 2010 Apr;239(4):1102-12.
Long-term consequences of Sox9 depletion on inner ear development.
Park BY, Saint-Jeannet JP.
Department of Animal Biology, School of Veterinary Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
The transcription factor Sox9 has been implicated in inner ear formation in
several species. To investigate the long-term consequences of Sox9 depletion on
inner ear development we analyzed the inner ear architecture of Sox9-depleted
Xenopus tadpoles generated by injection of increasing amounts of Sox9 morpholino
antisense oligonucleotides. We found that Sox9-depletion resulted in major
defects in the development of vestibular structures, semicircular canals and
utricle, while the ventrally located saccule was less severely affected in these
embryos. Consistent with this phenotype, we observed a specific loss of the
dorsal expression of Wnt3a expression in the otic vesicle of Sox9 morphants,
associated with an increase in cell death and a reduction in cell proliferation
in the region of the presumptive otic epithelium. We propose that, in addition to
its early role in placode specification, Sox9 is also required for the
maintenance of progenitors in the otic epithelium.
PMCID: PMC2847000
PMID: 20201105 [PubMed - in process]
3. PLoS One. 2010 Feb 23;5(2):e9377.
Canal cristae growth and fiber extension to the outer hair cells of the mouse ear
require Prox1 activity.
Fritzsch B, Dillard M, Lavado A, Harvey NL, Jahan I.
Department of Biology, University of Iowa, Iowa City, Iowa, United States of
America. bernd-fritzsch@uiowa.edu
BACKGROUND: The homeobox gene Prox1 is required for lens, retina, pancreas,
liver, and lymphatic vasculature development and is expressed in inner ear
supporting cells and neurons. METHODOLOGY/PRINCIPAL FINDINGS: We have
investigated the role of Prox1 in the developing mouse ear taking advantage of
available standard and conditional Prox1 mutant mouse strains using Tg(Pax2-Cre)
and Tg(Nes-Cre). A severe reduction in the size of the canal cristae but not of
other vestibular organs or the cochlea was identified in the E18.5
Prox1(Flox/Flox); Tg(Pax2-Cre) mutant ear. In these mutant embryos, hair cell
differentiated; however, their distribution pattern was slightly disorganized in
the cochlea where the growth of type II nerve fibers to outer hair cells along
Prox1 expressing supporting cells was severely disrupted. In the case of
Nestin-Cre, we found that newborn Prox1(Flox/Flox); Tg(Nestin-Cre) exhibit only a
disorganized innervation of outer hair cells despite apparently normal cellular
differentiation of the organ of Corti, suggesting a cell-autonomous function of
Prox1 in neurons. CONCLUSIONS/SIGNIFICANCE: These results identify a dual role of
Prox1 during inner ear development; growth of the canal cristae and fiber
guidance of Type II fibers along supporting cells in the cochlea.
PMCID: PMC2826422
PMID: 20186345 [PubMed - in process]
4. Int J Otolaryngol. 2009;2009:972565. Epub 2010 Jan 27.
The importance of saccular function to motor development in children with hearing
impairments.
Shall MS.
Department of Physical Therapy, Virginia Commonwealth University, P.O. Box
980224, Richmond, VA 23298-0224, USA.
Children with hearing deficits frequently have delayed motor development. The
purpose of this study was to evaluate saccular function in children with hearing
impairments using the Vestibular Evoked Myogenic Potential (VEMP). The impact of
the saccular hypofunction on the timely maturation of normal balance strategies
was examined using the Movement Assessment Battery for Children (Movement ABC).
Thirty-three children with bilateral severe/profound hearing impairment between 4
and 7 years of age were recruited from a three-state area. Approximately half of
the sample had one or bilateral cochlear implants, one used bilateral hearing
aids, and the rest used no amplification. Parents reported whether the hearing
impairment was diagnosed within the first year or after 2 years of age. No VEMP
was evoked in two thirds of the hearing impaired (HI) children in response to the
bone-conducted stimulus. Children who were reportedly hearing impaired since
birth had significantly poorer scores when tested with the Movement ABC.
PMCID: PMC2817862
PMID: 20148080 [PubMed - in process]
5. J Rehabil Res Dev. 2009;46(6):797-810.
Auditory and vestibular dysfunction associated with blast-related traumatic brain
injury.
Fausti SA, Wilmington DJ, Gallun FJ, Myers PJ, Henry JA.
Department of Veterans Affairs (VA) Rehabilitation Research and Development
Service, National Center for Rehabilitative Auditory Research, Portland VA
Medical Center, Portland, OR 97239, USA.
The dramatic escalation of blast exposure in military deployments has created an
unprecedented amount of traumatic brain injury (TBI) and associated auditory
impairment. Auditory dysfunction has become the most prevalent individual
service-connected disability, with compensation totaling more than 1 billion
dollars annually. Impairment due to blast can include peripheral hearing loss,
central auditory processing deficits, vestibular impairment, and tinnitus. These
deficits are particularly challenging in the TBI population, as symptoms can be
mistaken for posttraumatic stress disorder, mental-health issues, and cognitive
deficits. In addition, comorbid factors such as attention, cognition, neuronal
loss, noise toxicity, etc., can confound assessment, causing misdiagnosis.
Furthermore, some auditory impairments, such as sensorineural hearing loss, will
continue to progress with age, unlike many other injuries. In the TBI population,
significant clinical challenges are the accurate differentiation of auditory and
vestibular impairments from multiple, many times overlapping, symptoms and the
development of multidisciplinary rehabilitation strategies to improve treatment
outcomes and quality of life for these patients.
PMID: 20104403 [PubMed - indexed for MEDLINE]
6. BMC Ear Nose Throat Disord. 2009 Dec 29;9:13.
An evaluation of the cost-effectiveness of booklet-based self-management of
dizziness in primary care, with and without expert telephone support.
Yardley L, Kirby S, Barker F, Little P, Raftery J, King D, Morris A, Mullee M.
School of Psychology, University of Southampton, Highfield, Southampton, UK.
BACKGROUND: Dizziness is a very common symptom that often leads to reduced
quality of life, anxiety and emotional distress, loss of fitness, lack of
confidence in balance, unsteadiness and an increased risk of falling. Most dizzy
patients are managed in primary care by reassurance and medication to suppress
symptoms. Trials have shown that chronic dizziness can be treated effectively in
primary care using a self-help booklet to teach patients vestibular
rehabilitation exercises that promote neurological adaptation and skill and
confidence in balance. However, brief support from a trained nurse was provided
in these trials, and this model of managing dizzy patients has not been taken up
due to a lack of skills and resources in primary care. The aim of this trial is
to evaluate two new alternative models of delivery that may be more feasible and
cost-effective. METHODS/DESIGN: In a single blind two-centre pragmatic controlled
trial, we will randomise 330 patients from 30 practices to a) self-help booklet
with telephone support from a vestibular therapist, b) self-help booklet alone,
c) routine medical care. Symptoms, disability, handicap and quality of life will
be assessed by validated questionnaires administered by post at baseline,
immediately post-treatment (3 months), and at one year follow-up. The study is
powered to test our primary hypothesis, that the self-help booklet with telephone
support will be more effective than routine care. We will also explore the
effectiveness of the booklet without any support, and calculate the costs of
treatment in each arm. DISCUSSION: If our trial indicates that patients can
cost-effectively manage their dizziness in primary care, then it can be easily
rolled out to relieve the symptoms of the many patients in primary care who
currently have chronic, untreated, disabling dizziness. Treatment in primary care
may reduce the development of psychological and physical sequelae that cause
handicap and require treatment. There is also the potential to reduce the cost to
the NHS of treating dizziness by reducing demand for referral to secondary care
for specialist assessment and treatment. TRIAL REGISTRATION: ClinicalTrials.gov
trial registration ID number: NCT00732797.
PMCID: PMC2810289
PMID: 20098640 [PubMed - in process]
7. Cases J. 2009 Dec 21;2:9367.
Migraine vestibulopathy in three families with idiopathic scoliosis: a case
series.
Uneri A, Polat S, Aydingoz O, Bursali A.
Department of Otorhinolaryngology, Balance Center, Acibadem Health Group
Koztayagi Hospital, Istanbul, 34742, Turkey.
INTRODUCTION: We assessed clinical and etiological association between vestibular
pathology and idiopathic scoliosis concerning seven members of three families
with idiopathic scoliosis. CASE PRESENTATION: The families were referred to
neurotology center for evaluation of balance problems. Patients were evaluated
thorough anamnesis to relevant vestibular and audiological studies in addition to
idiopathic scoliosis assessment. All evaluated scoliotic patients had clinical
manifestations of vestibular dysfunctions and migrainous headache. All of the
scoliotic patients (seven patients) in these three families were diagnosed as
migraine vestibulopathy. CONCLUSION: With the presentation of these three
families, we discussed the probable role of the vestibular dysfunctions including
migraine vestibulopathy in the development and progression of idiopathic
scoliosis.
PMCID: PMC2804012
PMID: 20062612 [PubMed - in process]
8. J Clin Sleep Med. 2009 Aug 15;5(4):374-5.
Association of idiopathic rapid eye movement sleep behavior disorder in an adult
with persistent, childhood onset rhythmic movement disorder.
Xu Z, Anderson KN, Shneerson JM.
Westmead Hospital, Sydney, Australia.
We present a case of a 41-year-old man with the association of REM sleep behavior
disorder (RBD) and rhythmic movement disorder (RMD). The RMD had a childhood
onset and persisted into adulthood. The RMD worsened with the development of RBD
and has persisted despite successful treatment of RBD. However, the pathogenesis
of RMD remains unclear and the movements have been suggested to play a
maturational role as part of psychomotor development by stimulating the
vestibular apparatus. Current models underlying the control of REM sleep may need
to be refined to explain the observed association of RBD and RMD.
PMCID: PMC2725259
PMID: 19968018 [PubMed - indexed for MEDLINE]
9. PLoS One. 2009 Nov 11;4(11):e7786.
Disorganized innervation and neuronal loss in the inner ear of Slitrk6-deficient
mice.
Katayama K, Zine A, Ota M, Matsumoto Y, Inoue T, Fritzsch B, Aruga J.
Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science
Institute, Wako-shi, Saitama, Japan.
Slitrks are type I transmembrane proteins that share conserved leucine-rich
repeat domains similar to those in the secreted axonal guidance molecule Slit.
They also show similarities to Ntrk neurotrophin receptors in their
carboxy-termini, sharing a conserved tyrosine residue. Among 6 Slitrk family
genes in mammals, Slitrk6 has a unique expression pattern, with strong expression
in the sensory epithelia of the inner ear. We generated Slitrk6-knockout mice and
investigated the development of their auditory and vestibular sensory organs.
Slitrk6-deficient mice showed pronounced reduction in the cochlear innervation.
In the vestibule, the innervation to the posterior crista was often lost,
reduced, or sometimes misguided. These defects were accompanied by the loss of
neurons in the spiral and vestibular ganglia. Cochlear sensory epithelia from
Slitrk6-knockout mice have reduced ability in promoting neurite outgrowth of
spiral ganglion neurons. Indeed the Slitrk6-deficient inner ear showed a mild but
significant decrease in the expression of Bdnf and Ntf3, both of which are
essential for the innervation and survival of sensory neurons. In addition, the
expression of Ntrk receptors, including their phosphorylated forms was decreased
in Slitrk6-knockout cochlea. These results suggest that Slitrk6 promotes
innervation and survival of inner ear sensory neurons by regulating the
expression of trophic and/or tropic factors including neurotrophins from sensory
epithelia.
PMCID: PMC2777407
PMID: 19936227 [PubMed - indexed for MEDLINE]
10. Dev Biol. 2010 Feb 1;338(1):38-49. Epub 2009 Nov 10.
Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear.
Deng M, Pan L, Xie X, Gan L.
University of Rochester Flaum Eye Institute, University of Rochester, Rochester,
NY 14642, USA.
During development, compartmentalization of an early embryonic structure produces
blocks of cells with distinct properties and developmental potentials. The
auditory and vestibular components of vertebrate inner ears are derived from
defined compartments within the otocyst during embryogenesis. The vestibular
apparatus, including three semicircular canals, saccule, utricle, and their
associated sensory organs, detects angular and linear acceleration of the head
and relays the information through vestibular neurons to vestibular nuclei in the
brainstem. How the early developmental events manifest vestibular structures at
the molecular level is largely unknown. Here, we show that LMO4, a
LIM-domain-only transcriptional regulator, is required for the formation of
semicircular canals and their associated sensory cristae. Targeted disruption of
Lmo4 resulted in the dysmorphogenesis of the vestibule and in the absence of
three semicircular canals, anterior and posterior cristae. In Lmo4-null otocysts,
canal outpouches failed to form and cell proliferation was reduced in the
dorsolateral region. Expression analysis of the known otic markers showed that
Lmo4 is essential for the normal expression of Bmp4, Fgf10, Msx1, Isl1, Gata3,
and Dlx5 in the dorsolateral domain of the otocyst, whereas the initial
compartmentalization of the otocyst remains unaffected. Our results demonstrate
that Lmo4 controls the development of the dorsolateral otocyst into semicircular
canals and cristae through two distinct mechanisms: regulating the expression of
otic specific genes and stimulating the proliferation of the dorsolateral part of
the otocyst.
PMCID: PMC2812651
PMID: 19913004 [PubMed - indexed for MEDLINE]
11. Acta Otolaryngol. 2010 Apr;130(4):420-8.
The intravestibular source of the vestibular aqueduct. II: its structure and
function clarified by a developmental study of the intra-skeletal channels of the
otic capsule.
Michaels L, Soucek S, Linthicum F.
University College London Ear Institute and Department of Cellular Pathology, UCL
Medical School, University Street, London. UK. l.michaels@ucl.ac.uk
CONCLUSION: A developmental histologic study of the otic capsule indicates that
it grows a system of lamellar bone with abundant interconnecting intraosseous
channels. These include the 'cartilage canals' in the cartilage model, the
chondro-osseous and Haversian-like (Volkmann's) canals in the ossified otic
capsule, the fissula ante fenestram, which seems to function as a lifelong
manufacturer of the latter two channels, and the inner layer (vestibular arch) of
the vestibular aqueduct, which is a complex series of Volkmann's canals and
microcanals. Chemical changes, possibly produced by breakdown of cells within the
channels, may provide a homeostatic environment for the functions of hearing and
balance that take place in the endolymphatic fluid. OBJECTIVES: We studied the
development of the otic capsule to clarify the cellular appearances that we had
previously described in the normal vestibular arch and the changes in that
structure in Ménière's disease. METHODS: Step sections from 84 temporal bones,
including those from fetuses, children and adults from a variety of ages were
examined histologically. RESULTS: Cartilage canals, bringing blood vessels and
mesenchymal cells from perichondrium to the depths of the cartilage model to
mediate ossification, are found early in fetal life and disappear when
ossification is complete at about 24 weeks. The otic capsule is formed of
chondro-osseous canals, which are composed of trabeculae of mineralized cartilage
lacunae containing mesenchymal cells that undergo ossification (globuli ossei);
also Volkmann's canals (like Haversian canals in long bones but
multidirectional), which are produced from osteoblasts. The lumina of the latter
frequently link up with chondro-osseous canals. Lamellar bone forms the
background of the otic capsule. The fissula ante fenestram is present from early
in the cartilage model and then throughout life. It appears to mediate bone
production and the new formation of chondro-osseous channels and Volkmann's
canals. The internal layer of the vestibular aqueduct (vestibular arch) is seen
in the cartilage model of the otic capsule (present in early fetal life) as a
vascular layer of perichondrally derived connective tissue (not cartilage)
surrounding the endolymphatic duct. When endochondral ossification starts, the
bone from the adjoining cochlear and vestibular sides embrace this connective
tissue layer to form the outer bony layer of the vestibular aqueduct. Osteoblasts
then fill the inner layer with lamellar bone and macro- and mini-Volkmann's
canals. At 1 year osteoblasts in the walls of macro-Volkmann's canals,
proliferating thereafter throughout life, produce large numbers of microcanals.
It is possible that slow breakdown of these osteoblasts and of similar cells in
the canals of the otic capsule proper may contribute to the homeostasis of the
endolymphatic duct and that of the rest of the membranous labyrinth,
respectively.
PMCID: PMC2865695
PMID: 19895329 [PubMed - in process]
12. Diagn Interv Radiol. 2009 Dec;15(4):239-41. Epub 2009 Oct 27.
Posttraumatic labyrinthitis ossificans with perilymphatic fistulization.
Aralaşmak A, Dinçer E, Arslan G, Cevikol C, Karaali K.
Department of Radiology, Akdeniz University School of Medicine, Antalya, Turkey.
aysearalasmak@hotmail.com
Labyrinthitis ossificans is fibrosis or ossification of the membranous labyrinth.
Tympanogenic, meningogenic, and hematogenous etiologies are more common than
trauma in the development of labyrinthitis ossificans. We present a case
complaining of right-sided hearing loss and symptoms of otitis media and
positional vertigo resulting from perilymphatic fistulization. Imaging revealed
labyrinthitis ossificans secondary to temporal bone fracture crossing through the
otic capsule.
PMID: 19862674 [PubMed - indexed for MEDLINE]
13. Nan Fang Yi Ke Da Xue Xue Bao. 2009 Oct;29(10):2118-21.
[Cochlear implant in patients with congenital malformation of the inner ear]
[Article in Chinese]
Wan LC, Guo MH, Qian YH, Liu SX, Zhang HZ, Chen SJ, Chen H, Gong J.
Department of Otolaryngology, Zhujiang Hospital, Southern Medical University,
Guangzhou 510282, China. wanliangcai@126.com
OBJECTIVE: To summarize the clinical experience with multi-channel cochlear
implantation in patients with inner ear malformations and evaluate and the
outcomes of speech rehabilitation. METHODS: A retrospective study was conducted
in 295 patients receiving cochlear implantation from 1998 to 2007, including 25
patients with large vestibular aqueduct syndrome (LVAS), 9 with Modini
malformation, and 5 with common cavity deformity. All the patients received the
Nucleus24 cochlear implants. In LVAS cases, 4 had Nucleus 24R (ST) implants, 8
had Contuor implants, 10 had Contuor Advance, and the remaining cases used
Nucleus24(M) straight-electrode implants. RESULTS: Severe gusher appeared in 3
cases of LVAS, and perilymph fluctuation were seen in other 15 cases. Four
patients with Mondini malformation and 2 with common cavity malformation also
experienced severe gusher, but the electrodes were inserted smoothly in all the
patients without postoperative facial paralysis or cerebrospinal fluid leakage.
The hearing threshold in these patients was similar to that in patients with
normal cochlear structure. After speech rehabilitation for over 6 months, the
abilities of speech discrimination and spoken language improved in all the cases
in comparison with the preoperative lingual functions. CONCLUSION: Multi-channel
cochlear implantation can be performed in patients with inner ear malformation,
but should not be attempted in patients with poor cochlear and cochlear nerve
development. A comprehensive pre-operative radiographic and audiological
evaluation is essential.
PMID: 19861281 [PubMed - in process]
14. Acta Otorrinolaringol Esp. 2009 Sep-Oct;60(5):318-24. Epub 2009 Jul 24.
[CSF fistulae following surgery for cerebellopontine angle tumours and their
relationship with the body mass index]
[Article in Spanish]
Diaz Anadon A, Lassaletta L, Roda JM, Gavilán Bouzas J.
Servicio de Otorrinolaringología, Hospital Universitario La Paz, España.
aguedadiazanadon@gmail.com
INTRODUCTION: The most frequent complication after vestibular schwannoma surgery
is cerebrospinal fluid (CSF) fistula. MATERIAL AND METHODS: Retrospective study
of 170 patients who had vestibular schwannoma (163) or other tumours in the
cerebello pontine angle (CPA) (7). Resection was carried out using different
approaches: retrosigmoid (66%), translabyrinthine (24%), middle cranial fossa
(5%) and others (5%). We studied the day of onset, location and treatment of the
CSF leaks, and the influence of demographic, radiological and clinical variables,
including Body Mass Index. RESULTS: 27 patients developed a CSF fistula (15.9%):
15 were incisional (8.8%), 8 patients developed CSF rhinorrhea (4.7%), 1 CSF
otorrhea (0.6%) and 3 a combination of the above (1.8%). We controlled 11 CSF
fistulae with bed rest and compressive dressings (6.5%), 7 required lumbar
drainage (4.1%), 2 lumbar drainage and wound closure with local anaesthesia
(1.2%) and 7 patients required returning to the operating room under general
anaesthesia (4.1%). There was not a significant relationship between the
apparition of CSF and tumour size, type of approach, age or body mass index
(BMI). CONCLUSIONS: Despite the great development and new surgical techniques,
CSF fistulae are still a frequent complication after VS surgery. There might be
other aetiological factors such as intracranial pressure. There was no
significant relationship between CSF fistula and BMI. Adequate management and
early conservative measures led to reduced reintervention rates of less than 5%
in all patients.
PMID: 19814983 [PubMed - indexed for MEDLINE]
15. J Neurosci. 2009 Oct 7;29(40):12477-83.
Vestibular asymmetry as the cause of idiopathic scoliosis: a possible answer from
Xenopus.
Lambert FM, Malinvaud D, Glaunès J, Bergot C, Straka H, Vidal PP.
Centre National de la Recherche Scientifique , Unité Mixte de Recherche
7060-Université Paris Descartes, 75006 Paris, France.
Human idiopathic scoliosis is characterized by severe deformations of the spine
and skeleton. The occurrence of vestibular-related deficits in these patients is
well established but it is unclear whether a vestibular pathology is the common
cause for the scoliotic syndrome and the gaze/posture deficits or if the latter
behavioral deficits are a consequence of the scoliotic deformations. A possible
vestibular origin was tested in the frog Xenopus laevis by unilateral removal of
the labyrinthine endorgans at larval stages. After metamorphosis into young adult
frogs, X-ray images and three-dimensional reconstructed micro-computer
tomographic scans of the skeleton showed deformations similar to those of
scoliotic patients. The skeletal distortions consisted of a curvature of the
spine in the frontal and sagittal plane, a transverse rotation along the body
axis and substantial deformations of all vertebrae. In terrestrial vertebrates,
the initial postural syndrome after unilateral labyrinthectomy recovers over time
and requires body weight-supporting limb proprioceptive information. In an
aquatic environment, however, this information is absent. Hence, the
lesion-induced asymmetric activity in descending spinal pathways and the
resulting asymmetric muscular tonus persists. As a consequence the mostly
cartilaginous skeleton of the frog tadpoles progressively deforms. Lack of limb
proprioceptive signals in an aquatic environment is thus the element, which links
the Xenopus model with human scoliosis because a comparable situation occurs
during gestation in utero. A permanently imbalanced activity in descending
locomotor/posture control pathways might be the common origin for the observed
structural and behavioral deficits in humans as in the different animal models of
scoliosis.
PMID: 19812323 [PubMed - indexed for MEDLINE]
16. Theor Biol Med Model. 2009 Sep 1;6:19.
A model analysis of static stress in the vestibular membranes.
Pender DJ.
Department of Otolaryngology, Columbia University Medical Center New York, USA.
djp2@columbia.edu
BACKGROUND: The scheme of the core vestibular membranes, consisting of serially
connected utricle, ampulla and semicircular canal, first appeared hundreds of
millions of years ago in primitive fish and has remained largely unchanged during
the subsequent course of evolution. The labyrinths of higher organisms build on
this core structure, with the addition of the phylogenetically newer membrane
structures, namely, saccule, lagena and cochlea. An analysis of static stress in
these core vestibular membranes may contribute to a better understanding of the
role of stress in the evolution of derivative membrane structures over the long
term as well as the short-term membrane distortions seen in Meniere's disease.
METHODS: A model of these core vestibular membranes is proposed in order to
analyze the distribution of stress in the walls of the component chambers. The
model uses basic geometrical elements of hollow cylinders and spheres to emulate
the actual structures. These model elements lend themselves to a mathematical
analysis of static stress in their membranes. RESULTS: Hoop stress, akin to the
stress in hoops used to reinforce barrel walls, is found to be the predominant
stress in the model membranes. The level of hoop stress depends not only on
pressure but as well on a geometric stress factor that incorporates membrane
shape, thickness and curvature. This result implies that hoop stress may be
unevenly distributed in the membranes of the several vestibular chambers due to
variations in these dimensional parameters. These results provide a theoretical
framework for appraising hoop stress levels in any vestibular labyrinth whose
dimensions are known. CONCLUSION: Static hoop stress disparities are likely to
exist in the vestibular membranes given their complex physical configurations.
Such stress disparities may contribute to the development of membrane pathologies
as seen in Meniere's Disease. They may also factor in the evolutionary
development of other derivative membrane structures such as the saccule, the
lagena, and the cochlea found in higher animals.
PMCID: PMC2745365
PMID: 19723316 [PubMed - indexed for MEDLINE]
17. J Neurosci. 2009 Aug 26;29(34):10779-83.
Long-term potentiation in the rat medial vestibular nuclei depends on locally
synthesized 17beta-estradiol.
Grassi S, Frondaroli A, Dieni C, Scarduzio M, Pettorossi VE.
Department of Internal Medicine, Section of Human Physiology, University of
Perugia, I-06126 Perugia, Italy. sgrassi@unipg.it
In male rat brainstem slices, we investigated the involvement of locally
synthesized 17beta-estradiol (E(2)) in the induction in the medial vestibular
nucleus (MVN) of long-term potentiation (LTP) by high-frequency stimulation (HFS)
of the primary vestibular afferents. We demonstrated that the blockade of
aromatase by letrozole or of E(2) receptors (ERalpha and ERbeta) by ICI 182,780
prevented the HFS-induced LTP of the N1 wave of the evoked field potential (FP)
without affecting baseline responses. Only prolonged afferent activation could
induce low LTP. In contrast, HFS applied under a combined blockade of GABA(A)
receptors and aromatase or ERs was still able to induce LTP, but it was
significantly lower and slower. These findings demonstrate that E(2) does not
have a tonic influence on the activity of the MVN neurons and provide the first
evidence of the crucial role played by local synthesis of E(2) in inducing LTP.
We suggest that the synthesis of E(2) occurs after aromatase activation during
HFS and facilitates the development of vestibular synaptic plasticity by
influencing glutamate and GABA transmission.
PMID: 19710328 [PubMed - indexed for MEDLINE]
18. Tidsskr Nor Laegeforen. 2009 Aug 13;129(15):1469-73.
[Neurofibromatosis type 2 and auditory brainstem implantation]
[Article in Norwegian]
Elvsåshagen T, Solyga V, Bakke SJ, Heiberg A, Kerty E.
Avdeling for nevropsykiatri og psykosomatisk medisin, Nevroklinikken, Oslo
universitetssykehus, Rikshospitalet 0027 Oslo og Institutt for psykiatri Det
medisinske fakultet, Universitetet i Oslo, Norway.
torbjorn.elvsashagen@rikshospitalet.no
BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare and severe autosomal
dominant disorder caused by mutations in a tumour suppressor gene. This article
reviews NF2 and its treatment with auditory brainstem implantation. MATERIAL AND
METHODS: The review is based on the authors' experience with the disease and
literature identified through a non-systematic search of PubMed. RESULTS: NF2 is
caused by loss-of-normal function of the tumour suppressor protein merlin. Merlin
normally suppresses cell growth and proliferation. The clinical picture is
dominated by neurological symptoms, caused by multiple tumours - mainly
schwannomas and meningeomas. The hallmark of the disease is development of
bilateral vestibular schwannomas, and the most common presenting symptom in
adults is progressive hearing loss. Presenile cataract, ocular motility
disorders, peripheral neuropathy and skin tumours are other common findings. The
majority of patients become deaf, many patients become severely disabled and life
expectancy is reduced. The goal of management is conservation of function and
maintenance of quality of life. Auditory brainstem implants stimulate the
cochlear nucleus directly and provide substantial auditory benefits to patients
with NF2. INTERPRETATION: A multidisciplinary approach in specialty centres is
recommended. Management by an experienced team reduces mortality and improves
outcome after surgery. Auditory brainstem implantation is an important part of
the hearing rehabilitation in these patients. Emerging knowledge of the molecular
disease mechanisms offers hope for new therapeutic strategies.
PMID: 19690597 [PubMed - indexed for MEDLINE]
19. Development. 2009 Aug;136(16):2837-48.
Nkcc1 (Slc12a2) is required for the regulation of endolymph volume in the otic
vesicle and swim bladder volume in the zebrafish larva.
Abbas L, Whitfield TT.
MRC Centre for Developmental and Biomedical Genetics and Department of Biomedical
Science, University of Sheffield, Sheffield, UK.
Endolymph is the specialised extracellular fluid present inside the inner ear. In
mammals, disruptions to endolymph homeostasis can result in either collapse or
distension of the endolymphatic compartment in the cochlea, with concomitant
hearing loss. The zebrafish little ears (lte) mutant shows a collapse of the otic
vesicle in the larva, apparently owing to a loss of endolymphatic fluid in the
ear, together with an over-inflation of the swim bladder. Mutant larvae display
signs of abnormal vestibular function by circling and swimming upside down. The
two available alleles of lte are homozygous lethal: mutant larvae fail to thrive
beyond 6 days post-fertilisation. Patterning of the otic vesicle is apparently
normal. However, the expression of several genes thought to play a role in
endolymph production is downregulated, including the sodium-potassium-chloride
cotransporter gene nkcc1 (slc12a2) and several Na(+)/K(+)-ATPase channel subunit
genes. We show here that lte mutations correspond to lesions in nkcc1. Each
allele has a point mutation that disrupts splicing, leading to frame shifts in
the coding region that predict the generation of truncated products. Endolymph
collapse in the lte/nkcc1 mutant shows distinct parallels to that seen in mouse
Nkcc1 mutants, validating zebrafish as a model for the study of endolymph
disorders. The collapse in ear volume can be ameliorated in the to27d allele of
lte by injection of a morpholino that blocks splicing at an ectopic site
introduced by the mutation. This exemplifies the use of morpholinos as potential
therapeutic agents for genetic disease.
PMCID: PMC2730410
PMID: 19633174 [PubMed - indexed for MEDLINE]
20. Orphanet J Rare Dis. 2009 Jun 19;4:16.
Neurofibromatosis type 2 (NF2): a clinical and molecular review.
Evans DG.
Medical Genetics Research Group, Regional Genetics Service and National Molecular
Genetics Reference Laboratory, Central Manchester Foundation Trust, St Mary's
Hospital, Manchester M130JH, UK. dgr.evans@virgin.net
Neurofibromatosis type 2 (NF2) is a tumour-prone disorder characterised by the
development of multiple schwannomas and meningiomas. Prevalence (initially
estimated at 1: 200,000) is around 1 in 60,000. Affected individuals inevitably
develop schwannomas, typically affecting both vestibular nerves and leading to
hearing loss and deafness. The majority of patients present with hearing loss,
which is usually unilateral at onset and may be accompanied or preceded by
tinnitus. Vestibular schwannomas may also cause dizziness or imbalance as a first
symptom. Nausea, vomiting or true vertigo are rare symptoms, except in late-stage
disease. The other main tumours are schwannomas of the other cranial, spinal and
peripheral nerves; meningiomas both intracranial (including optic nerve
meningiomas) and intraspinal, and some low-grade central nervous system
malignancies (ependymomas). Ophthalmic features are also prominent and include
reduced visual acuity and cataract. About 70% of NF2 patients have skin tumours
(intracutaneous plaque-like lesions or more deep-seated subcutaneous nodular
tumours). Neurofibromatosis type 2 is a dominantly inherited tumour
predisposition syndrome caused by mutations in the NF2 gene on chromosome 22.
More than 50% of patients represent new mutations and as many as one-third are
mosaic for the underlying disease-causing mutation. Although truncating mutations
(nonsense and frameshifts) are the most frequent germline event and cause the
most severe disease, single and multiple exon deletions are common. A strategy
for detection of the latter is vital for a sensitive analysis. Diagnosis is based
on clinical and neuroimaging studies. Presymptomatic genetic testing is an
integral part of the management of NF2 families. Prenatal diagnosis and
pre-implantation genetic diagnosis is possible. The main differential diagnosis
of NF2 is schwannomatosis. NF2 represents a difficult management problem with
most patients facing substantial morbidity and reduced life expectancy. Surgery
remains the focus of current management although watchful waiting with careful
surveillance and occasionally radiation treatment have a role. Prognosis is
adversely affected by early age at onset, a higher number of meningiomas and
having a truncating mutation. In the future, the development of tailored drug
therapies aimed at the genetic level are likely to provide huge improvements for
this devastating condition.
PMCID: PMC2708144
PMID: 19545378 [PubMed - indexed for MEDLINE]
21. J Korean Med Sci. 2009 May;24 Suppl 2:S258-66. Epub 2009 May 31.
Development of guideline for rating the physical impairment of otolaryngologic
field.
Park CW, Do NY, Rha KS, Chung SM, Kwon YJ; Korean Academy of Medical Sciences.
Department of Otolaryngology, College of Medicine, Hanyang University, Seoul,
Korea. cwpark@hanyang.ac.kr
We develop a guideline for rating the physical impairment of otolaryngologic
fields. Assessment of hearing disturbance and tinnitus required physical
examination, pure tone audiometry, speech audiometry, impedance audiometry,
brainstem evoked response audiometry, Bekesy audiometry, otoacoustic emission
test, and imaging examination. History taking, physical examination, and
radiological examination for the vestibular organ and brain, righting reflex
test, electronystagmography, and caloric test are taken for evaluation of balance
disorder. Olfactory function tests include University of Pennsylvania Smell
Identification test, Connecticut Chemosensory Clinical Research Center test, T
and T olfactometry and Korean Version of Sniffin's Sticks test. Medical history
and physical examination is mandatory to evaluatezseverity of respiration
difficulty. Examinations include flexible fiberoptic nasopharyngoscope,
bronchoscopy, simple soft-tissue radiography films of upper airway and high
resolution computed tomography. Evaluation of mastication and swallowing are
history taking, physical examination, examination for upper jaw, lower jaw, and
temporomandibular joint, dental examination and radiological studies. Endoscopy
and esophagography are also needed. Voice disorder is evaluated based on physical
examination, oral pharynx and larynx endoscopy, larynx stroboscopy, hearing
assessment, laryngeal electromyography, sound analysis test, aerodynamic test,
electroglottography, and radiologic examination. Articulation disorder is
assessed by picture consonant articulation test. These are position articulation
test, Lee-Kim Korean articulation picture and speech intelligibility assessment.
PMCID: PMC2690073
PMID: 19503682 [PubMed - indexed for MEDLINE]
22. BMC Dev Biol. 2009 May 29;9:31.
Tbx1 and Brn4 regulate retinoic acid metabolic genes during cochlear
morphogenesis.
Braunstein EM, Monks DC, Aggarwal VS, Arnold JS, Morrow BE.
Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park
Avenue, Bronx, New York 10461, USA. ebraunst@aecom.yu.edu
BACKGROUND: In vertebrates, the inner ear is comprised of the cochlea and
vestibular system, which develop from the otic vesicle. This process is regulated
via inductive interactions from surrounding tissues. Tbx1, the gene responsible
for velo-cardio-facial syndrome/DiGeorge syndrome in humans, is required for ear
development in mice. Tbx1 is expressed in the otic epithelium and adjacent
periotic mesenchyme (POM), and both of these domains are required for inner ear
formation. To study the function of Tbx1 in the POM, we have conditionally
inactivated Tbx1 in the mesoderm while keeping expression in the otic vesicle
intact. RESULTS: Conditional mutants (TCre-KO) displayed malformed inner ears,
including a hypoplastic otic vesicle and a severely shortened cochlear duct,
indicating that Tbx1 expression in the POM is necessary for proper inner ear
formation. Expression of the mesenchyme marker Brn4 was also lost in the TCre-KO.
Brn4-;Tbx1+/-embryos displayed defects in growth of the distal cochlea. To
identify a potential signal from the POM to the otic epithelium, expression of
retinoic acid (RA) catabolizing genes was examined in both mutants. Cyp26a1
expression was altered in the TCre-KO, while Cyp26c1 showed reduced expression in
both TCre-KO and Brn4-;Tbx1+/- embryos. CONCLUSION: These results indicate that
Tbx1 expression in the POM regulates cochlear outgrowth potentially via control
of local retinoic acid activity.
PMCID: PMC2700094
PMID: 19476657 [PubMed - indexed for MEDLINE]
23. BMC Ear Nose Throat Disord. 2009 May 16;9:2.
Long-term symptoms in dizzy patients examined in a university clinic.
Wilhelmsen K, Ljunggren AE, Goplen F, Eide GE, Nordahl SH.
Department of Public Health and Primary Health Care, Section for Physiotherapy
Science, University of Bergen, Bergen, Norway. Kjersti.Wilhelmsen@hib.no
BACKGROUND: The long-term course of dizziness was investigated combining medical
chart and survey data. The survey was undertaken median (interquartile range
(IQR)) 4.6 (4.3) years after the initial medical examination. METHODS: Chart data
comprised sex, age, diagnosis, symptom duration, postural sway and neck pain.
Survey data comprised symptom severity assessed by the Vertigo Symptom Scale -
Short Form (VSS-SF), and data regarding current state of dizziness, medication,
neck pain and other chronic conditions. RESULTS: The sample consisted of 503
patients, the mean (standard deviation (SD)) age was 50.0 (11.6) years, women
being slightly overrepresented (60%). Severe problems with dizziness (VSS-SF mean
(SD) 13.9, (10.8)) were indicated in the total group and in 5 of 6 diagnostic
sub-groups. Vertigo/balance- and autonomic/anxiety-related symptoms were present
in all groups. Current dizziness was confirmed by 73% who had significantly more
severe problems than the non-dizzy (VSS-SF mean (SD): 17.2 (10.1) versus 5.0
(7.3)). Symptoms were related to vertigo/balance more than to autonomic/anxiety
(test of interaction p < 0.001).Based on simple logistic regression analysis,
sex, symptom duration, neck pain, sway and diagnoses predicted dizziness. Symptom
duration and neck pain remained predictors in the adjusted analysis. Age, symptom
duration, neck pain, sway and diagnoses predicted vertigo/balance-related
dizziness in both regression analyses. Sex, neck pain and sway predicted
development of autonomic/anxiety-related dizziness according to simple regression
analysis, while only neck pain remained a significant predictor in the adjusted
analysis. With respect to diagnosis, simple regression analysis showed
significant reduced likelihood for development of dizziness in all vestibular
sub-groups when compared to the non-otogenic dizziness group. With respect to
vertigo/balance- and autonomic/anxiety-related symptoms, the implication of
diagnostic belonging varied. No effect of diagnoses was seen in adjusted
analyses. CONCLUSION: The majority of patients had persistent and severe problems
with dizziness. The wait-and-see attitude before referral to specialist
institutions may be questioned. Early, active movements seem necessary, and
attention should be paid to the presence of neck pain. Diagnoses had limited
prognostic value. Questionnaire-based evaluations could assist in classification
and identification of type of dizziness and thereby provide a better basis for
specific rehabilitation.
PMCID: PMC2693507
PMID: 19445693 [PubMed]
24. PLoS Genet. 2009 May;5(5):e1000480. Epub 2009 May 8.
Synaptojanin1 is required for temporal fidelity of synaptic transmission in hair
cells.
Trapani JG, Obholzer N, Mo W, Brockerhoff SE, Nicolson T.
Howard Hughes Medical Institute, Oregon Health and Science University, Portland,
OR, USA.
To faithfully encode mechanosensory information, auditory/vestibular hair cells
utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The
molecular basis of SV release and consequent recycling of membrane in hair cells
has not been fully explored. Here, we report that comet, a gene identified in an
ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the
lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells
revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel
activity but not mechanotransduction. Synaptojanin has been previously implicated
in SV recycling; therefore, we tested synaptic transmission at hair-cell
synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively
normal spike rates when hair cells were mechanically stimulated for a short
period of time at 20 Hz. In contrast, a sharp decline in the rate of firing
occurred during prolonged stimulation at 20 Hz or stimulation at a higher
frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were
available for release. Consistent with this result, we observed that stimulated
mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in
comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired
phase locking of the postsynaptic activity to the mechanical stimulus. Following
prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells
displayed a striking delay in the recovery of spontaneous activity. Collectively,
the data suggest that Synj1 is critical for retrieval of membrane in order to
maintain the quantity, timing of fusion, and spontaneous release properties of
SVs at hair-cell ribbon synapses.
PMCID: PMC2673039
PMID: 19424431 [PubMed - indexed for MEDLINE]
25. Acta Otorrinolaringol Esp. 2009 Mar-Apr;60(2):131-40.
[An update on the treatment of vestibular schwannoma]
[Article in Spanish]
Lassaletta L, Gavilán J.
Servicio de Otorrinolaringología, Hospital Universitario La Paz, Madrid, Spain.
luikilassa@yahoo.com
The increase in the diagnosis of ever smaller vestibular schwannomas (VS), the
fact that many tumours can be observed with serial MRI, and the development of
radiosurgery as an alternative to microsurgery have led the neurotologic surgeon
to a new global approach to patients with VS. On the other hand, the spread of
internet-based information sources, often with biased or incomplete information,
makes counselling patients with VS a challenging task. This study provides an
overview of the natural history of these tumours and the main therapeutic
options: observation, surgery and radiosurgery, with comments on their
indications, advantages and disadvantages. Due to the completely different
approach and peculiar features of bilateral VS in patients with type II
neurofibromatosis, these are excluded.
PMID: 19401081 [PubMed - indexed for MEDLINE]
26. Dev Biol. 2009 Apr 15;328(2):285-96. Epub 2009 Feb 2.
Catweasel mice: a novel role for Six1 in sensory patch development and a model
for branchio-oto-renal syndrome.
Bosman EA, Quint E, Fuchs H, Hrabé de Angelis M, Steel KP.
The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton
CB10 1SA, UK.
Large-scale mouse mutagenesis initiatives have provided new mouse mutants that
are useful models of human deafness and vestibular dysfunction. Catweasel is a
novel N-ethyl-N-nitrosourea (ENU)-induced mutation. Heterozygous catweasel mutant
mice exhibit mild headtossing associated with a posterior crista defect. We
mapped the catweasel mutation to a critical region of 13 Mb on chromosome 12
containing the Six1, -4 and -6 genes. We identified a basepair substitution in
exon 1 of the Six1 gene that changes a conserved glutamic acid (E) at position
121 to a glycine (G) in the Six1 homeodomain. Cwe/Cwe animals lack Preyer and
righting reflexes, display severe headshaking and have severely truncated cochlea
and semicircular canals. Cwe/Cwe animals had very few hair cells in the utricle,
but their ampullae and cochlea were devoid of any hair cells. Bmp4, Jag1 and Sox2
expression were largely absent at early stages of sensory development and NeuroD
expression was reduced in the developing vestibulo-acoustic ganglion. Lastly we
show that Six1 genetically interacts with Jag1. We propose that the catweasel
phenotype is due to a hypomorphic mutation in Six1 and that catweasel mice are a
suitable model for branchio-oto-renal syndrome. In addition Six1 has a pivotal
role in early sensory patch development and may act in the same genetic pathway
as Jag1.
PMCID: PMC2682643
PMID: 19389353 [PubMed - indexed for MEDLINE]
27. PLoS Genet. 2009 Apr;5(4):e1000455. Epub 2009 Apr 17.
Phoenix is required for mechanosensory hair cell regeneration in the zebrafish
lateral line.
Behra M, Bradsher J, Sougrat R, Gallardo V, Allende ML, Burgess SM.
National Human Genome Research Institute, National Institutes of Health,
Bethesda, Maryland, USA.
In humans, the absence or irreversible loss of hair cells, the sensory
mechanoreceptors in the cochlea, accounts for a large majority of acquired and
congenital hearing disorders. In the auditory and vestibular neuroepithelia of
the inner ear, hair cells are accompanied by another cell type called supporting
cells. This second cell population has been described as having stem cell-like
properties, allowing efficient hair cell replacement during embryonic and
larval/fetal development of all vertebrates. However, mammals lose their
regenerative capacity in most inner ear neuroepithelia in postnatal life.
Remarkably, reptiles, birds, amphibians, and fish are different in that they can
regenerate hair cells throughout their lifespan. The lateral line in amphibians
and in fish is an additional sensory organ, which is used to detect water
movements and is comprised of neuroepithelial patches, called neuromasts. These
are similar in ultra-structure to the inner ear's neuroepithelia and they share
the expression of various molecular markers. We examined the regeneration process
in hair cells of the lateral line of zebrafish larvae carrying a retroviral
integration in a previously uncharacterized gene, phoenix (pho). Phoenix mutant
larvae develop normally and display a morphologically intact lateral line.
However, after ablation of hair cells with copper or neomycin, their regeneration
in pho mutants is severely impaired. We show that proliferation in the supporting
cells is strongly decreased after damage to hair cells and correlates with the
reduction of newly formed hair cells in the regenerating phoenix mutant
neuromasts. The retroviral integration linked to the phenotype is in a novel gene
with no known homologs showing high expression in neuromast supporting cells.
Whereas its role during early development of the lateral line remains to be
addressed, in later larval stages phoenix defines a new class of proteins
implicated in hair cell regeneration.
PMCID: PMC2662414
PMID: 19381250 [PubMed - indexed for MEDLINE]
28. J Assoc Res Otolaryngol. 2009 Sep;10(3):321-40. Epub 2009 Apr 17.
Hes5 expression in the postnatal and adult mouse inner ear and the drug-damaged
cochlea.
Hartman BH, Basak O, Nelson BR, Taylor V, Bermingham-McDonogh O, Reh TA.
Department of Biological Structure, University of Washington, Seattle, WA 98195,
USA.
The Notch signaling pathway is known to have multiple roles during development of
the inner ear. Notch signaling activates transcription of Hes5, a homologue of
Drosophila hairy and enhancer of split, which encodes a basic helix-loop-helix
transcriptional repressor. Previous studies have shown that Hes5 is expressed in
the cochlea during embryonic development, and loss of Hes5 leads to
overproduction of auditory and vestibular hair cells. However, due to technical
limitations and inconsistency between previous reports, the precise spatial and
temporal pattern of Hes5 expression in the postnatal and adult inner ear has
remained unclear. In this study, we use Hes5-GFP transgenic mice and in situ
hybridization to report the expression pattern of Hes5 in the inner ear. We find
that Hes5 is expressed in the developing auditory epithelium of the cochlea
beginning at embryonic day 14.5 (E14.5), becomes restricted to a particular
subset of cochlear supporting cells, is downregulated in the postnatal cochlea,
and is not present in adults. In the vestibular system, we detect Hes5 in
developing supporting cells as early as E12.5 and find that Hes5 expression is
maintained in some adult vestibular supporting cells. In order to determine the
effect of hair cell damage on Notch signaling in the cochlea, we damaged cochlear
hair cells of adult Hes5-GFP mice in vivo using injection of kanamycin and
furosemide. Although outer hair cells were killed in treated animals and
supporting cells were still present after damage, supporting cells did not
upregulate Hes5-GFP in the damaged cochlea. Therefore, absence of Notch-Hes5
signaling in the normal and damaged adult cochlea is correlated with lack of
regeneration potential, while its presence in the neonatal cochlea and adult
vestibular epithelia is associated with greater capacity for plasticity or
regeneration in these tissues; which suggests that this pathway may be involved
in regulating regenerative potential.
PMCID: PMC2757554
PMID: 19373512 [PubMed - indexed for MEDLINE]
29. BMC Neurosci. 2009 Mar 25;10:27.
Proteomic and functional analysis of NCS-1 binding proteins reveals novel
signaling pathways required for inner ear development in zebrafish.
Petko JA, Kabbani N, Frey C, Woll M, Hickey K, Craig M, Canfield VA, Levenson R.
Department of Pharmacology, Penn State College of Medicine, 500 University Drive,
Hershey PA 17033, USA. jac554@psu.edu
BACKGROUND: The semicircular canals, a subdivision of the vestibular system of
the vertebrate inner ear, function as sensors of angular acceleration. Little is
currently known, however, regarding the underlying molecular mechanisms that
govern the development of this intricate structure. Zebrafish represent a
particularly tractable model system for the study of inner ear development. This
is because the ear can be easily visualized during early embryogenesis, and both
forward and reverse genetic techniques are available that can be applied to the
discovery of novel genes that contribute to proper ear development. We have
previously shown that in zebrafish, the calcium sensing molecule neuronal calcium
sensor-1 (NCS-1) is required for semicircular canal formation. The function of
NCS-1 in regulating semicircular canal formation has not yet been elucidated.
RESULTS: We initiated a multistep functional proteomic strategy to identify
neuronal calcium sensor-1 (NCS-1) binding partners (NBPs) that contribute to
inner ear development in zebrafish. By performing a Y2H screen in combination
with literature and database searches, we identified 10 human NBPs. BLAST
searches of the zebrafish EST and genomic databases allowed us to clone zebrafish
orthologs of each of the human NBPs. By investigating the expression profiles of
zebrafish NBP mRNAs, we identified seven that were expressed in the developing
inner ear and overlapped with the ncs-1a expression profile. GST pulldown
experiments confirmed that selected NBPs interacted with NCS-1, while
morpholino-mediated knockdown experiments demonstrated an essential role for
arf1, pi4kbeta, dan, and pink1 in semicircular canal formation. CONCLUSION: Based
on their functional profiles, the hypothesis is presented that
Ncs-1a/Pi4kbeta/Arf1 form a signaling pathway that regulates secretion of
molecular components, including Dan and Bmp4, that are required for development
of the vestibular apparatus. A second set of NBPs, consisting of Pink1, Hint2,
and Slc25a25, are destined for localization in mitochondria. Our findings reveal
a novel signalling pathway involved in development of the semicircular canal
system, and suggest a previously unrecognized role for NCS-1 in mitochondrial
function via its association with several mitochondrial proteins.
PMCID: PMC2679751
PMID: 19320994 [PubMed - indexed for MEDLINE]
30. Acta Otorrinolaringol Esp. 2009 Jan-Feb;60(1):49-53.
[Contribution of the vestibular evoked myogenic potentials to the study of the
vestibular neuritis]
[Article in Spanish]
Lesmas Navarro MJ, Pérez Garrigues H, Morera Pérez C, Piqueras A.
Servicio de Otorrinolaringología, Hospital Universitario La Fe, Valencia, España.
INTRODUCTION: Until recently, the only tests available to provide information
about vestibular function were caloric and kinetic tests, which only give us
information about the external semicircular canal and the superior vestibular
nerve. In recent years the development of vestibular evoked myogenic potentials
has allowed us to assess the saccule and the inferior vestibular nerve. Our aim
is, by studying the caloric test results as well as the vestibular evoked
myogenic potentials in patients with Vestibular Neuritis, to determine whether
they have involvement of the superior, inferior or both vestibular nerves.
MATERIAL AND METHODS: Retrospective study of 9 patients with Vestibular Neuritis
admitted to a tertiary care hospital. We studied them by means of anamnesis,
otoneurological clinical examination, caloric test and vestibular evoked myogenic
potentials. Their clinical progress after admission and any residual instability
were also studied. RESULTS: Women were more affected (66.6 %) than males. The
mean age for presentation of the disease was 53.8 +/- 14.0 years. Hospital stays
lasted for 5.7 +/- 3.2 days. After their crises, they suffered from instability
for 122 +/- 114 days. Four cases were diagnosed as Complete Vestibular Neuritis
and five as Superior Vestibular Neuritis. P13 wave latency was normal in all
cases. There were no differences between the groups in terms of the length of
hospital stay nor residual instability. CONCLUSIONS: Nowadays, vestibular evoked
myogenic potentials make it possible to advance further in the study of
Vestibular Neuritis. Complete and superior vestibular neuritis are much more
frequent than inferior vestibular neuritis. Clinical behaviour is similar in the
sub-types found.
PMID: 19268130 [PubMed - indexed for MEDLINE]
31. Med Oral Patol Oral Cir Bucal. 2009 Mar 1;14(3):E146-52.
A descriptive study of 113 unerupted supernumerary teeth in 79 pediatric patients
in Barcelona.
Ferrés-Padró E, Prats-Armengol J, Ferrés-Amat E.
Service of Oral and Maxillofacial Surgery, Hospital de Nens de Barcelona,
Barcelona, Spain.
Unerupted supernumerary teeth, depending on the morphology, number and
distribution can give rise to various alterations in the eruption and development
of those permanent teeth to which they are related. OBJECTIVES: We aimed to make
an epidemiological and descriptive study of the clinical characteristics of
patients in Barcelona, their surgical treatment and how said treatment was
hindered. MATERIALS AND METHODS: A descriptive study including 113 supernumerary
teeth from 79 healthy pediatric patients between 5 and 19 years of age, which
underwent surgery in our hospital during a 2 year period (May 2005 / May 2007),
taking into account the variables of personal data, gender, age, location,
number, morphology, position-axis, radiological study, surgical treatment,
related pathologies, and surgical complications. RESULTS: Male patients (51) were
more frequently affected than female (28) patients mainly within the central
incisors-mesiodens (53.16%), in which the unique form (68.52%) predominates in
conoid morphology (69.62%). Surgical treatment was done by palatal/lingual
extraction (49.37%), with few surgical complications (only 1 case of
post-surgical bleeding). CONCLUSION: Incidence in supernumerary teeth is higher
among male patients (ratio M:F of 1.82:1). They are most frequently located in
the maxilla (82%), specifically, in the premaxilla (77%). Most cases presented
only one supernumerary tooth (68.5%) and, in multiple cases, the premolar region
is predominant. The conoid shape is the commonest morphology (69.62%). Surgical
extraction, was done by palatal/lingual in 49.37% of the cases, as opposed to the
vestibular approach in 45.57%.
PMID: 19242396 [PubMed - indexed for MEDLINE]
32. J Exp Biol. 2009 Mar;212(Pt 5):639-47.
Plasma membrane calcium ATPase required for semicircular canal formation and
otolith growth in the zebrafish inner ear.
Cruz S, Shiao JC, Liao BK, Huang CJ, Hwang PP.
Institute of Fisheries Science, College of Life Science, National Taiwan
University, Taipei, Taiwan.
Fish otoliths consist of >90% calcium carbonate, the accretion of which depends
on acellular endolymph. This study confirms the presence of plasma membrane
calcium ATPase 1a isoform (Atp2b1a) in the auditory and vestibular system of a
teleost fish. As shown by in situ hybridization, zebrafish atp2b1a is expressed
mainly in larval otic placode and lateral-line neuromast as well as in the hair
cells within the adult zebrafish inner ear chamber. Zebrafish atp2b1a knockdown
by antisense morpholinos reduced the number of hair cells and produced
malformation of semicircular canals and smaller otoliths. These defects coincide
with unbalanced body orientation. The formation of smaller otoliths in atp2b1a
morphants may stem from an impairment of calcium supply in the endolymph.
However, otolith formation persists in most morphants, suggesting that other
zebrafish Atp2b isoforms or paracellular pathways may also transport calcium into
the endolymph. These results suggest that Atp2b1a plays an important role for
normal development of the auditory and vestibular system as well as calcium
transport in the inner ear of zebrafish.
PMID: 19218514 [PubMed - indexed for MEDLINE]
33. PLoS One. 2009;4(2):e4368. Epub 2009 Feb 3.
A late role for bmp2b in the morphogenesis of semicircular canal ducts in the
zebrafish inner ear.
Hammond KL, Loynes HE, Mowbray C, Runke G, Hammerschmidt M, Mullins MC, Hildreth
V, Chaudhry B, Whitfield TT.
MRC Centre for Developmental and Biomedical Genetics and Department of Biomedical
Science, University of Sheffield, Sheffield, United Kingdom.
BACKGROUND: The Bone Morphogenetic Protein (BMP) genes bmp2 and bmp4 are
expressed in highly conserved patterns in the developing vertebrate inner ear. It
has, however, proved difficult to elucidate the function of BMPs during ear
development as mutations in these genes cause early embryonic lethality. Previous
studies using conditional approaches in mouse and chicken have shown that Bmp4
has a role in semicircular canal and crista development, but there is currently
no direct evidence for the role of Bmp2 in the developing inner ear.
METHODOLOGY/PRINCIPAL FINDINGS: We have used an RNA rescue strategy to test the
role of bmp2b in the zebrafish inner ear directly. Injection of bmp2b or smad5
mRNA into homozygous mutant swirl (bmp2b(-/-)) embryos rescues the early
patterning defects in these mutants and the fish survive to adulthood. As
injected RNA will only last, at most, for the first few days of embryogenesis,
all later development occurs in the absence of bmp2b function. Although rescued
swirl adult fish are viable, they have balance defects suggestive of vestibular
dysfunction. Analysis of the inner ears of these fish reveals a total absence of
semicircular canal ducts, structures involved in the detection of angular motion.
All other regions of the ear, including the ampullae and cristae, are present and
appear normal. Early stages of otic development in rescued swirl embryos are also
normal. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate a critical late role
for bmp2b in the morphogenesis of semicircular canals in the zebrafish inner ear.
This is the first demonstration of a developmental role for any gene during
post-embryonic stages of otic morphogenesis in the zebrafish. Despite differences
in the early stages of semicircular canal formation between zebrafish and
amniotes, the role of Bmp2 in semicircular canal duct outgrowth is likely to be
conserved between different vertebrate species.
PMCID: PMC2629815
PMID: 19190757 [PubMed - indexed for MEDLINE]
34. J Neurosci. 2009 Jan 14;29(2):575-87.
Complementary actions of BDNF and neurotrophin-3 on the firing patterns and
synaptic composition of motoneurons.
Davis-López de Carrizosa MA, Morado-Díaz CJ, Tena JJ, Benítez-Temiño B, Pecero
ML, Morcuende SR, de la Cruz RR, Pastor AM.
Departamento de Fisiología y Zoología, Facultad de Biología, Universidad de
Sevilla, Sevilla, Spain.
Neurotrophins, as target-derived factors, are essential for neuronal survival
during development, but during adulthood, their scope of actions widens to become
also mediators of synaptic and morphological plasticity. Target disconnection by
axotomy produces an initial synaptic stripping ensued by synaptic rearrangement
upon target reinnervation. Using abducens motoneurons of the oculomotor system as
a model for axotomy, we report that trophic support by brain-derived neurotrophic
factor (BDNF), neurotrophin-3 (NT-3) or a mixture of both, delivered to the stump
of severed axons, results in either the prevention of synaptic stripping when
administered immediately after lesion or in a promotion of reinnervation of
afferents to abducens motoneurons once synaptic stripping had occurred, in
concert with the recovery of synaptic potentials evoked from the vestibular
nerve. Synaptotrophic effects, however, were larger when both neurotrophins were
applied together. The axotomy-induced reduction in firing sensitivities related
to eye movements were also restored to normal values when BDNF and NT-3 were
administered, but discharge characteristics recovered in a complementary manner
when only one neurotrophin was used. This is the first report to show selective
retrograde trophic dependence of circuit-driven firing properties in vivo
indicating that NT-3 restored the phasic firing, whereas BDNF supported the tonic
firing of motoneurons during eye movement performance. Therefore, our data report
a link between the synaptotrophic actions of neurotrophins, retrogradely
delivered, and the alterations of neuronal firing patterns during motor
behaviors. These trophic actions could be responsible, in part, for synaptic
rearrangements that alter circuit stability and synaptic balance during plastic
events of the brain.
PMID: 19144857 [PubMed - indexed for MEDLINE]
35. Dev Neurobiol. 2009 Feb 1-15;69(2-3):191-202.
Expression of the Pax2 transcription factor is associated with vestibular
phenotype in the avian inner ear.
Warchol ME, Richardson GP.
Fay and Carl Simons Center for the Biology of Hearing and Deafness, Washington
University School of Medicine, St. Louis, MO 63110, USA. warcholm@ent.wustl.edu
The paired-domain transcription factor Pax2 is involved in many facets of inner
ear development, but relatively little is known about the expression or function
of Pax2 in the mature ear. In this study, we have used immunohistochemical
methods to characterize the expression patterns of Pax2 in the sensory organs of
inner ears from posthatch chicks. Immunoreactivity for Pax2 was observed in the
nuclei of most hair cells and supporting cells in the vestibular organs. In
contrast, Pax2 expression in the chick cochlea was limited to hair cells located
in the very distal (low frequency) region. We then used organotypic cultures of
the chick utricle to examine changes in Pax2 expression in response to ototoxic
injury and during hair cell regeneration. Treatment with streptomycin resulted in
the loss of most Pax2 immunoreactivity from the lumenal (hair cell) stratum of
the utricle. During the early phases of regeneration, moderate Pax2 expression
was maintained in the nuclei of proliferating supporting cells. Expression of
Pax2 in the hair cell stratum recovered in parallel with hair cell regeneration.
The results indicate that Pax2 continues to be expressed in the mature avian ear,
and that its expression pattern is correlated with a vestibular phenotype.
PMCID: PMC2731773
PMID: 19130600 [PubMed - indexed for MEDLINE]
36. Front Hum Neurosci. 2008;2:17. Epub 2008 Dec 3.
The vestibular component in out-of-body experiences: a computational approach.
Schwabe L, Blanke O.
Adaptive and Regenerative Software Systems, Department of Computer Science and
Electrical Engineering Rostock, Germany. lars.schwabe@uni-rostock.de
Neurological evidence suggests that disturbed vestibular processing may play a
key role in triggering out-of-body experiences (OBEs). Little is known about the
brain mechanisms during such pathological conditions, despite recent experimental
evidence that the scientific study of such experiences may facilitate the
development of neurobiological models of a crucial aspect of self-consciousness:
embodied self-location. Here we apply Bayesian modeling to vestibular processing
and show that OBEs and the reported illusory changes of self-location and
translation can be explained as the result of a mislead Bayesian inference, in
the sense that ambiguous bottom-up signals from the vestibular otholiths in the
supine body position are integrated with a top-down prior for the upright body
position, which we measure during natural head movements. Our findings have
relevance for self-location and translation under normal conditions and suggest
novel ways to induce and study experimentally both aspects of bodily
self-consciousness in healthy subjects.
PMCID: PMC2610253
PMID: 19115017 [PubMed]
37. AJNR Am J Neuroradiol. 2009 May;30(5):992-4. Epub 2008 Nov 27.
Communicating hydrocephalus after gamma knife radiosurgery for vestibular
schwannoma: an MR imaging study.
Cauley KA, Ratkovits B, Braff SP, Linnell G.
Department of Radiology, University of Vermont College of Medicine, Burlington,
VT, USA. keithcauley@hotmail.com
Vestibular schwannomas are common, and gamma knife radiosurgery is a treatment
option of symptomatic tumors. Hydrocephalus may be a complication of gamma knife
treatment of vestibular schwannoma, though the cause-and-effect relationship can
be debated because tumors can cause hydrocephalus without treatment. We present
an MR imaging study of an unusual case of communicating hydrocephalus after gamma
knife radiosurgery of a vestibular schwannoma in which the timeline of events
strongly suggests that gamma knife played a contributory role in the development
of hydrocephalus. We discuss risk factors for the development of hydrocephalus
after radiation therapy and the role of MR CSF cine-flow study in the evaluation
of treatment options for hydrocephalus in this setting.
PMID: 19039040 [PubMed - indexed for MEDLINE]
38. Methods Mol Biol. 2009;493:311-21.
Identification of transcription factor-DNA interactions using chromatin
immunoprecipitation assays.
Nie L, Vázquez AE, Yamoah EN.
Department of Otolaryngology, Center for Neuroscience, University of California,
Davis CA, USA.
Expression of almost every gene is regulated at the transcription level.
Therefore, transcriptional factor Transcription factors, consequently, have
marked effects on the fate of a cell by establishing the gene expression patterns
that determine biological processes. In the auditory and vestibular systems,
transcription factors have been found to be responsible for development, cell
growth, and apoptosis. It is vital to identify the transcription factor target
genes and the mechanisms by which transcription factors control and guide gene
expression and regulation pathways. Compared with earlier methods devised to
study transcription factor-DNA interactions, the advantage of the chromatin
immunoprecipitation (ChIP) assay is that the interaction of a transcription
factor with its target genes is captured in the native context of chromatin in
living cells. Therefore, ChIP base assays are powerful tools to identify the
direct interaction of transcription factors and their target genes in vivo. More
importantly, ChIP assays have been used in combination with molecular biology
techniques, such as PCR and real time PCR, gene cloning, and DNA microarrays, to
determine the interaction of transcription factor-DNA from a few potential
individual targets to genome-wide surveys.
PMCID: PMC2822710
PMID: 18839356 [PubMed - indexed for MEDLINE]
39. Methods Mol Biol. 2009;493:141-62.
Isolation of sphere-forming stem cells from the mouse inner ear.
Oshima K, Senn P, Heller S.
Department of Otolaryngology-HNS, Stanford University School of Medicine,
Stanford, CA, USA.
The mammalian inner ear has very limited ability to regenerate lost sensory hair
cells. This deficiency becomes apparent when hair cell loss leads to hearing loss
as a result of either ototoxic insult or the aging process. Coincidently, with
this inability to regenerate lost hair cells, the adult cochlea does not appear
to harbor cells with a proliferative capacity that could serve as progenitor
cells for lost cells. In contrast, adult mammalian vestibular sensory epithelia
display a limited ability for hair cell regeneration, and sphere-forming cells
with stem cell features can be isolated from the adult murine vestibular system.
The neonatal inner ear, however, does harbor sphere-forming stem cells residing
in cochlear and vestibular tissues. Here, we provide protocols to isolate
sphere-forming stem cells from neonatal vestibular and cochlear sensory epithelia
as well as from the spiral ganglion. We further describe procedures for sphere
propagation, cell differentiation, and characterization of inner ear cell types
derived from spheres. Sphere-forming stem cells from the mouse inner ear are an
important tool for the development of cellular replacement strategies of damaged
inner ears and are a bona fide progenitor cell source for transplantation
studies.
PMCID: PMC2861714
PMID: 18839346 [PubMed - indexed for MEDLINE]
40. J Vis. 2008 Aug 22;8(11):15.1-10.
Development of visually driven postural reactivity: a fully immersive virtual
reality study.
Greffou S, Bertone A, Hanssens JM, Faubert J.
Visual Psychophysics and Perception Laboratory, School of Optometry, University
of Montreal, Montreal, Quebec, Canada. selma.greffou@umontreal.ca
The objective of this study was to investigate the development of visually driven
postural regulation in typically developing children of different ages.
Thirty-two typically developing participants from 5 age groups (5-7 years, 8-11
years, 12-15 years, 16-19 years, or 20-25 years) were asked to stand within a
virtual tunnel that oscillated in an anterior-posterior fashion at three
different frequencies (0.125, 0.25, and 0.5 Hz). Body sway (BS) and postural
perturbations (as measured by velocity root mean squared or vRMS) were measured.
Most of the 5- to 7-year-old participants (67%) were unable to remain standing
during the dynamic conditions. For older participants, BS decreased significantly
with age for all frequencies. Moreover, vRMS decreased significantly from the 8-
to 11- through 16- to 19-years age groups (greatest decreases for 0.5 Hz,
followed by 0.25-Hz and 0.125-Hz conditions). No difference of frequency or
instability was found between the 16- to 19- and 20- to 25-year-old groups for
most conditions. Results suggest an over-reliance on visual input relative to
proprioceptive and vestibular inputs on postural regulation at young ages (5-7
years). The finding that vRMS decreased significantly with age before stabilizing
between 16 and 19 years suggests an important transitory period for sensorimotor
development within this age range.
PMID: 18831609 [PubMed - indexed for MEDLINE]
41. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14609-14. Epub 2008 Sep 15.
A catechol-O-methyltransferase that is essential for auditory function in mice
and humans.
Du X, Schwander M, Moresco EM, Viviani P, Haller C, Hildebrand MS, Pak K,
Tarantino L, Roberts A, Richardson H, Koob G, Najmabadi H, Ryan AF, Smith RJ,
Müller U, Beutler B.
Department of Genetics, Institute for Childhood and Neglected Diseases, The
Scripps Research Institute, La Jolla, CA 92037, USA.
We have identified a previously unannotated catechol-O-methyltranferase (COMT),
here designated COMT2, through positional cloning of a chemically induced
mutation responsible for a neurobehavioral phenotype. Mice homozygous for a
missense mutation in Comt2 show vestibular impairment, profound sensorineuronal
deafness, and progressive degeneration of the organ of Corti. Consistent with
this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear.
COMT2 enzymatic activity is significantly reduced by the missense mutation,
suggesting that a defect in catecholamine catabolism underlies the auditory and
vestibular phenotypes. Based on the studies in mice, we have screened DNA from
human families and identified a nonsense mutation in the human ortholog of the
murine Comt2 gene that causes nonsyndromic deafness. Defects in catecholamine
modification by COMT have been previously implicated in the development of
schizophrenia. Our studies identify a previously undescribed COMT gene and
indicate an unexpected role for catecholamines in the function of auditory and
vestibular sense organs.
PMCID: PMC2567147
PMID: 18794526 [PubMed - indexed for MEDLINE]
42. J Neurophysiol. 2008 Oct;100(4):2287-99. Epub 2008 Aug 27.
Molecular identity and functional properties of a novel T-type Ca2+ channel
cloned from the sensory epithelia of the mouse inner ear.
Nie L, Zhu J, Gratton MA, Liao A, Mu KJ, Nonner W, Richardson GP, Yamoah EN.
Center for Neuroscience, Program in Communication Science, University of
California, Davis, 1544 Newton Ct., Davis, CA 95618, USA.
The molecular identity of non-Cav1.3 channels in auditory and vestibular hair
cells has remained obscure, yet the evidence in support of their roles to promote
diverse Ca2+-dependent functions is indisputable. Recently, a transient Cav3.1
current that serves as a functional signature for the development and
regeneration of hair cells has been identified in the chicken basilar papilla.
The Cav3.1 current promotes spontaneous activity of the developing hair cell,
which may be essential for synapse formation. Here, we have isolated and
sequenced the full-length complementary DNA of a distinct isoform of Cav3.1 in
the mouse inner ear. The channel is derived from alternative splicing of exon14,
exon25A, exon34, and exon35. Functional expression of the channel in Xenopus
oocytes yielded Ca2+ currents, which have a permeation phenotype consistent with
T-type channels. However, unlike most multiion channels, the T-type channel does
not exhibit the anomalous mole fraction effect, possibly reflecting comparable
permeation properties of divalent cations. The Cav3.1 channel was expressed in
sensory and nonsensory epithelia of the inner ear. Moreover, there are profound
changes in the expression levels during development. The differential expression
of the channel during development and the pharmacology of the inner ear Cav3.1
channel may have contributed to the difficulties associated with identification
of the non-Cav1.3 currents.
PMCID: PMC2576198
PMID: 18753322 [PubMed - indexed for MEDLINE]
43. J Neurosci. 2008 Aug 6;28(32):8086-95.
Semicircular canal size determines the developmental onset of angular
vestibuloocular reflexes in larval Xenopus.
Lambert FM, Beck JC, Baker R, Straka H.
Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, Centre National de
Recherche Scientifique, Unité Mixte de Recherche 7060, Université Paris
Descartes, 75270 Paris Cedex 06, France.
Semicircular canals have been sensors of angular acceleration for 450 million
years. This vertebrate adaptation enhances survival by implementing postural and
visual stabilization during motion in a three-dimensional environment. We used an
integrated neuroethological approach in larval Xenopus to demonstrate that
semicircular canal dimensions, and not the function of other elements, determines
the onset of angular acceleration detection. Before angular vestibuloocular
function in either the vertical or horizontal planes, at stages 47 and 48,
respectively, each individual component of the vestibuloocular system was shown
to be operational: extraocular muscles could be activated, central neural
pathways were complete, and canal hair cells were capable of evoking graded
responses. For Xenopus, a minimum semicircular canal lumen radius of 60 microm
was necessary to permit endolymph displacement sufficient for sensor function at
peak accelerations of 400 degrees /s(2). An intra-animal comparison demonstrated
that this size is reached in the vertical canals earlier in development than in
the horizontal canals, corresponding to the earlier onset of vertical
canal-activated ocular motor behavior. Because size constitutes a biophysical
threshold for canal-evoked behavior in other vertebrates, such as zebrafish, we
suggest that the semicircular canal lumen and canal circuit radius are limiting
the onset of vestibular function in all small vertebrates. Given that the onset
of gravitoinertial acceleration detection precedes angular acceleration detection
by up to 10 d in Xenopus, these results question how the known precise spatial
patterning of utricular and canal afferents in adults is achieved during
development.
PMCID: PMC2647017
PMID: 18685033 [PubMed - indexed for MEDLINE]
44. Hum Mol Genet. 2008 Nov 1;17(21):3340-56. Epub 2008 Aug 4.
Eya1 gene dosage critically affects the development of sensory epithelia in the
mammalian inner ear.
Zou D, Erickson C, Kim EH, Jin D, Fritzsch B, Xu PX.
McLaughlin Research Institute for Biomedical Sciences, Great Falls, MT 59405,
USA.
Haploinsufficiency of the transcription co-activator EYA1 causes
branchio-oto-renal syndrome, congenital birth defects that account for as many as
2% of profoundly deaf children; however, the underlying cause for its dosage
requirement and its specific role in sensory cell development of the inner ear
are unknown. Here, an allelic series of Eya1 were generated to study the basis of
Eya1 dosage requirements for sensory organ development. Our results show
different threshold requirements for the level of Eya1 in different regions of
the inner ear. Short and disorganized hair cell sterocilia was observed in
wild-type/null heterozygous or hypomorphic/hypomorphic homozygous cochleae.
Patterning and gene-marker analyses indicate that in Eya1 hypomorphic/null
heterozygous mice, a reduction of Eya1 expression to 21% of normal level causes
an absence of cochlear and vestibular sensory formation. Eya1 is initially
expressed in the progenitors throughout the epithelium of all six sensory
regions, and later on during sensory cell differentiation, its expression becomes
restricted to the differentiating hair cells. We provide genetic evidence that
Eya1 activity, in a concentration-dependent manner, plays a key role in the
regulation of genes known to be important for sensory development. Furthermore,
we show that Eya1 co-localizes with Sox2 in the sensory progenitors and both
proteins physically interact. Together, our results indicate that Eya1 appears to
be upstream of very early events during the sensory organ development, hair cell
differentiation and inner-ear patterning. These results also provide a molecular
mechanism for understanding how hypomorphic levels of EYA1 cause inner-ear
defects in humans.
PMCID: PMC2722896
PMID: 18678597 [PubMed - indexed for MEDLINE]
45. J Comp Neurol. 2008 Oct 1;510(4):378-95.
Comprehensive Wnt-related gene expression during cochlear duct development in
chicken.
Sienknecht UJ, Fekete DM.
Department of Biological Sciences, Purdue University, West Lafayette, Indiana
47907, USA.
The avian cochlear duct houses both a vestibular and auditory sensory organ (the
lagena macula and basilar papilla, respectively), which each have a distinct
structure and function. Comparative mRNA in situ hybridization mapping conducted
over the time course of chicken cochlear duct development reveals that
Wnt-related gene expression is concomitant with various developmental processes
such as regionalization, convergent extension of the cochlear duct, cell fate
specification, synaptogenesis, and the establishment of planar cell polarity.
Wnts mostly originate from nonsensory tissue domains, whereas the sensory
primordia preferentially transcribe Frizzled receptors, suggesting that paracrine
Wnt signaling predominates in the cochlear duct. Superimposed over this is the
strong expression of two secreted Frizzled-related Wnt inhibitors that tend to
show complementary expression patterns. Frzb (SFRP3) is confined to the
nonsensory cochlear duct and the lagena macula, whereas SFRP2 is maintained in
the basilar papilla along with Fzd10 and Wnt7b. Flanking the basilar papilla are
Wnt7a, Wnt9a, Wnt11, and SFRP2 on the neural side and Wnt5a, Wnt5b, and Wnt7a on
the abneural side. The lateral nonsensory cochlear duct continuously expresses
Frzb and temporarily expresses Wnt6 and SFRP1. Characteristic for the entire
lagena is the expression of Frzb; in the lagena macula are Fzd1, Fzd7, and Wnt7b,
and in the nonsensory tissues are Wnt4 and Wnt5a. Auditory hair cells
preferentially express Fzd2 and Fzd9, whereas the main receptors expressed in
vestibular hair cells are Fzd1 and Fzd7, in addition to Fzd2 and Fzd9.
PMCID: PMC2566905
PMID: 18671253 [PubMed - indexed for MEDLINE]
46. Braz J Otorhinolaryngol. 2008 May-Jun;74(3):342-9.
Audiological study of an elderly Brazilian population.
do Carmo LC, Médicis da Silveira JA, Marone SA, D'Ottaviano FG, Zagati LL, Dias
von Söhsten Lins EM.
University of São Paulo Medical School, Brazil.
The Brazilian elderly population is growing, and already represents 8,6% of our
total population. Environmental factors, lifestyle, gender and genetics impact
the development of presbycusis, which reduces quality of life. AIM: investigate
audiologic and vestibular complaints in the elderly; perform tonal audiometry and
check to see if there are differences between genders. STUDY: Cross-sectional
clinical prospective study. MATERIALS AND METHODS: 320 elderly patients (160 men
and 160 women) were submitted to audiologic interview and tonal audiometry. The
results were statistically analyzed by the following methods: ANOVA, Mann-Whitney
and Chi-Squared. RESULTS: audiologic and vestibular complaints (hearing loss,
tinnitus, ear fullness, dizziness) were similar between the genders (except for
dizziness: p<0,05); tonal audiometry showed a significant difference, with
hearing loss in the high frequencies among men; and among women the curves were
descending and flat. These results were statistically significant (P<0,001).
CONCLUSION: our results lead us to conclude that, when the genders are compared,
hearing loss in the elderly has similar symptoms; however, there are significant
differences in tonal audiometry.
PMID: 18661006 [PubMed - indexed for MEDLINE]
47. J Neurosci. 2008 Jun 25;28(26):6633-41.
Jxc1/Sobp, encoding a nuclear zinc finger protein, is critical for cochlear
growth, cell fate, and patterning of the organ of corti.
Chen Z, Montcouquiol M, Calderon R, Jenkins NA, Copeland NG, Kelley MW,
Noben-Trauth K.
Sections on Neurogenetics, Laboratory of Molecular Biology, National Institute on
Deafness and Other Communication Disorders, National Institutes of Health,
Rockville, Maryland 20850, USA.
The mouse cochlea emerges from the ventral pole of the otocyst to form a one and
three-quarter coil. Little is known about the factors that control the growth of
the cochlea. Jackson circler (jc) is a recessive mutation causing deafness
resulting from a growth arrest of the cochlea duct at day 13.5 of embryonic
development. Here, we identify the vertebrate homolog of the Drosophila Sobp
(sine oculis-binding protein) gene (named Jxc1) in the jc locus. Jxc1 encodes a
nuclear protein that has two FCS-type zinc finger domains (PS51024) and bears
nuclear localization signals and highly conserved sequence motifs. Transiently
expressed wild-type protein is targeted to the nucleus, but mutant isoforms were
mislocalized in the cytoplasm. In jc mutants, the cellular patterning of the
organ of Corti is severely disrupted, exhibiting supernumerary hair cells at the
apex, showing mirror-image duplications of tunnel of Corti and inner hair cells,
and expressing ectopic vestibular-like hair cells within Kölliker's organ. Jxc1
mRNA was detected in inner ear sensory hair cells, supporting cells, and the
acoustic ganglia. Expression was also found in the developing retina, olfactory
epithelium, trigeminal ganglion, and hair follicles. Collectively, our data
support a role for Jxc1 in controlling a critical step in cochlear growth, cell
fate, and patterning of the organ of Corti.
PMCID: PMC2556235
PMID: 18579736 [PubMed - indexed for MEDLINE]
48. J Comp Neurol. 2008 Aug 20;509(6):661-76.
Espin actin-cytoskeletal proteins are in rat type I spiral ganglion neurons and
include splice-isoforms with a functional nuclear localization signal.
Sekerková G, Zheng L, Mugnaini E, Bartles JR.
Department of Cell and Molecular Biology, Northwestern University Feinberg School
of Medicine, Chicago, Illinois 60611, USA. g-sekerkova@northwestern.edu
The espins are Ca(2+)-resistant actin-bundling proteins that are enriched in hair
cell stereocilia and sensory cell microvilli. Here, we report a novel
localization of espins to a large proportion of rat type I spiral ganglion
neurons (SGNs) and their projections to the cochlear nucleus (CN). Moreover, we
show that a fraction of these espins is in the nucleus of SGNs owing to the
presence of splice-isoforms that contain a functional nuclear localization signal
(NLS). Espin antibody labeled approximately 83% of type I SGNs, and the labeling
intensity increased dramatically during early postnatal development. Type II SGNs
and vestibular ganglion neurons were unlabeled. In the CN, espin-positive
auditory nerve fibers showed a projection pattern typical of type I SGNs, with
intense labeling in the nerve root region and posteroventral CN (PVCN). The
anteroventral CN (AVCN) showed moderate labeling, whereas the dorsal CN showed
weak labeling that was restricted to the deep layer. Espin-positive synaptic
terminals were enriched around nerve root neurons and octopus cells in the PVCN
and were also found on globular bushy cells and multipolar neurons in the PVCN
and AVCN. SGNs expressed multiple espin transcripts and proteins, including
splice-isoforms that contain a nonapeptide, which is rich in positively charged
amino acids and creates a bipartite NLS. The nonapeptide was necessary to target
espin isoforms to the nucleus and was sufficient to target an unrelated protein
to the nucleus when joined with the upstream di-arginine-containing octapeptide.
The presence of cytoplasmic and nuclear espins in SGNs suggests additional roles
for espins in auditory neuroscience. Copyright 2008 Wiley-Liss, Inc.
PMCID: PMC2574652
PMID: 18551532 [PubMed - indexed for MEDLINE]
49. PLoS Genet. 2008 Apr 11;4(4):e1000050.
Bmp4 is essential for the formation of the vestibular apparatus that detects
angular head movements.
Chang W, Lin Z, Kulessa H, Hebert J, Hogan BL, Wu DK.
National Institute on Deafness and Other Communication Disorders, NIH, Rockville,
Maryland, United States of America.
Angular head movements in vertebrates are detected by the three semicircular
canals of the inner ear and their associated sensory tissues, the cristae. Bone
morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family
(TGF-beta), is conservatively expressed in the developing cristae in several
species, including zebrafish, frog, chicken, and mouse. Using mouse models in
which Bmp4 is conditionally deleted within the inner ear, as well as chicken
models in which Bmp signaling is knocked down specifically in the cristae, we
show that Bmp4 is essential for the formation of all three cristae and their
associated canals. Our results indicate that Bmp4 does not mediate the formation
of sensory hair and supporting cells within the cristae by directly regulating
genes required for prosensory development in the inner ear such as Serrate1
(Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista
formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr,
and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the
canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly.
Mechanisms involved in the formation of sensory organs of the vertebrate inner
ear are thought to be analogous to those regulating sensory bristle formation in
Drosophila. Our results suggest that, in comparison to sensory bristles, crista
formation within the inner ear requires an additional step of sensory and
non-sensory fate specification.
PMCID: PMC2274953
PMID: 18404215 [PubMed - indexed for MEDLINE]
50. Braz J Otorhinolaryngol. 2008 Jan-Feb;74(1):125-31.
Mobile phones: influence on auditory and vestibular systems.
Balbani AP, Montovani JC.
Faculdade de Medicina de Botucatu, UNESP, SP, Brazil. a_balbani@hotmail.com
Erratum in:
    Rev Bras Otorrinolaringol (Engl Ed). 2008 Mar-Apr;74(2):319.
Telecommunications systems emit radiofrequency, which is an invisible
electromagnetic radiation. Mobile phones operate with microwaves (450900 MHz in
the analog service, and 1,82,2 GHz in the digital service) very close to the
users ear. The skin, inner ear, cochlear nerve and the temporal lobe surface
absorb the radiofrequency energy. AIM: literature review on the influence of
cellular phones on hearing and balance. STUDY DESIGN: systematic review. METHODS:
We reviewed papers on the influence of mobile phones on auditory and vestibular
systems from Lilacs and Medline databases, published from 2000 to 2005, and also
materials available in the Internet. RESULTS: Studies concerning mobile phone
radiation and risk of developing an acoustic neuroma have controversial results.
Some authors did not see evidences of a higher risk of tumor development in
mobile phone users, while others report that usage of analog cellular phones for
ten or more years increase the risk of developing the tumor. Acute exposure to
mobile phone microwaves do not influence the cochlear outer hair cells function
in vivo and in vitro, the cochlear nerve electrical properties nor the vestibular
system physiology in humans. Analog hearing aids are more susceptible to the
electromagnetic interference caused by digital mobile phones. CONCLUSION: there
is no evidence of cochleo-vestibular lesion caused by cellular phones.
PMID: 18392513 [PubMed - indexed for MEDLINE]
51. J Neurosurg. 2008 Apr;108(4):751-6.
The vestibular aqueduct: site of origin of endolymphatic sac tumors.
Lonser RR, Baggenstos M, Kim HJ, Butman JA, Vortmeyer AO.
Surgical Neurology Branch, National Institute of Neurological Disorders and
Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
lonserr@ninds.nih.gov
Comment in:
    J Neurosurg. 2008 Sep;109(3):569-70; author reply 570.
OBJECT: Although endolymphatic sac tumors (ELSTs) frequently destroy the
posterior petrous bone and cause hearing loss, the anatomical origin of these
neoplasms is unknown. To determine the precise topographic origin of ELSTs, the
authors analyzed the imaging, operative, and pathological findings in patients
with von Hippel-Lindau disease (VHL) and ELSTs. METHODS: Consecutive VHL patients
with small (<or= 1.5 cm) ELSTs who underwent resection at the National Institutes
of Health were included. Clinical, imaging, operative, and pathological findings
were analyzed. RESULTS: Ten consecutive VHL patients (6 male and 4 female) with
10 small ELSTs (<or= 1.5 cm; 9 left, 1 right) were included. Serial imaging
captured the development of 6 ELSTs and revealed that they originated within the
intraosseous (vestibular aqueduct) portion of the endolymphatic duct/sac system.
Imaging just before surgery demonstrated that the epicenters of 9 ELSTs (1 ELST
was not visible on preoperative imaging) were in the vestibular aqueduct.
Inspection during surgery established that all 10 ELSTs were limited to the
intraosseous endolymphatic duct/sac and the immediately surrounding region.
Histological analysis confirmed tumor within the intraosseous portion (vestibular
aqueduct) of the endolymphatic duct/sac in all 10 patients. CONCLUSIONS: ELSTs
originate from endolymphatic epithelium within the vestibular aqueduct.
High-resolution imaging through the region of the vestibular aqueduct is
essential for diagnosis. Surgical exploration of the endolymphatic duct and sac
is required for complete resection.
PMCID: PMC2770700
PMID: 18377255 [PubMed - indexed for MEDLINE]
52. Acta Otorrinolaringol Esp. 2008 Feb;59(2):76-9.
[Peripheral vertigo classification. Consensus document. Otoneurology committee of
the Spanish otorhinolaryngology society (2003-2006)]
[Article in Spanish]
Morera C, Pérez H, Pérez N, Soto A; Comisión de Otoneurología de la Sociedad
Española de Otorrinolaringología.
Hospital Universitario la Fe, Universidad de Valencia, Valencia, España.
There are many different vertigo classifications and different denominations are
frequently used for the same clinical processes. The Otoneurology Committee of
the Spanish Society for Otorhinolaryngology and Head and Neck Pathology proposes
an eminently practical classification of peripheral vertigo to facilitate a
common terminology that can be easily used by the general ENT practitioners. The
methodology used has been by consensus within our Society and especially among
the most outstanding work groups in the area of otoneurology in Spain. Initially
vertigo is divided into single-episode vertigo and recurring attacks of vertigo,
and these are then sub-divided into 2 groups, depending on whether or not hearing
loss is present. Acute vertigo without hearing loss corresponds to vestibular
neuritis and if it is associated with hearing loss, it is due to labyrinthitis of
different aetiologies and cochleo-vestibular neuritis. Recurrent vertigos without
hearing loss are classified as induced, either by posture (BPPV) or pressure
(perilymphatic fistula), or as spontaneous, including migraine-associated
vertigo, metabolic vertigo, childhood paroxysmal vertigo and vertigo of vascular
causes (AITs, vertebral-basilar failure). Finally, recurrent vertigo with hearing
loss includes Ménière's disease and others such as vertigo-migraine (with hearing
loss), autoimmune pathology of the inner ear, syphilitic infection, and
perilymphatic fistula (with hearing loss).
PMID: 18341864 [PubMed - indexed for MEDLINE]
53. Development. 2008 Apr;135(8):1427-37. Epub 2008 Mar 13.
A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the
hair bundle in its cohesion, orientation and differential growth.
Lefèvre G, Michel V, Weil D, Lepelletier L, Bizard E, Wolfrum U, Hardelin JP,
Petit C.
Unité de Génétique des Déficits Sensoriels, UMRS587 INSERM-Université Paris VI,
Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France.
The planar polarity and staircase-like pattern of the hair bundle are essential
to the mechanoelectrical transduction function of inner ear sensory cells.
Mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15
or sans cause Usher syndrome type I (USH1, characterized by congenital deafness,
vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans
and hair bundle disorganization in mice. Whether the USH1 proteins are involved
in common hair bundle morphogenetic processes is unknown. Here, we show that
mouse models for the five USH1 genetic forms share hair bundle morphological
defects. Hair bundle fragmentation and misorientation (25-52 degrees mean
kinociliary deviation, depending on the mutant) were detected as early as
embryonic day 17. Abnormal differential elongation of stereocilia rows occurred
in the first postnatal days. In the emerging hair bundles, myosin VIIa, the
actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium
lateral link components cadherin 23 and protocadherin 15, all concentrated at
stereocilia tips, in accordance with their known in vitro interactions. Soon
after birth, harmonin-b switched from the tip of the stereocilia to the upper end
of the tip link, which also comprises cadherin 23 and protocadherin 15. This
positional change did not occur in mice deficient for cadherin 23 or
protocadherin 15. We suggest that tension forces applied to the early lateral
links and to the tip link, both of which can be anchored to actin filaments via
harmonin-b, play a key role in hair bundle cohesion and proper orientation for
the former, and in stereociliary elongation for the latter.
PMID: 18339676 [PubMed - indexed for MEDLINE]
54. Dev Dyn. 2008 Apr;237(4):941-52.
The transmembrane inner ear (tmie) gene contributes to vestibular and lateral
line development and function in the zebrafish (Danio rerio).
Shen YC, Jeyabalan AK, Wu KL, Hunker KL, Kohrman DC, Thompson DL, Liu D, Barald
KF.
Department of Cell and Developmental Biology, University of Michigan Medical
School, Ann Arbor, Michigan 48109-2200, USA.
The inner ear is a complex organ containing sensory tissue, including hair cells,
the development of which is not well understood. Our long-term goal is to
discover genes critical for the correct formation and function of the inner ear
and its sensory tissue. A novel gene, transmembrane inner ear (Tmie), was found
to cause hearing-related disorders when defective in mice and humans. A
homologous tmie gene in zebrafish was cloned and its expression characterized
between 24 and 51 hours post-fertilization. Embryos injected with morpholinos
(MO) directed against tmie exhibited circling swimming behavior (approximately
37%), phenocopying mice with Tmie mutations; semicircular canal formation was
disrupted, hair cell numbers were reduced, and maturation of electrically active
lateral line neuromasts was delayed. As in the mouse, tmie appears to be required
for inner ear development and function in the zebrafish and for hair cell
maturation in the vestibular and lateral line systems as well. (c) 2008
Wiley-Liss, Inc.
PMID: 18330929 [PubMed - indexed for MEDLINE]
55. Behav Neurosci. 2008 Feb;122(1):224-32.
Orbital spaceflight during pregnancy shapes function of mammalian vestibular
system.
Ronca AE, Fritzsch B, Bruce LL, Alberts JR.
Department of Obstetrics and Gynecology, Wake Forest University School of
Medicine, Winston-Salem, NC 27157, USA. aronca@wfubmc.edu
Pregnant rats were flown on the NASA Space Shuttle during the early developmental
period of their fetuses' vestibular apparatus and onset of vestibular function.
The authors report that prenatal spaceflight exposure shapes vestibular-mediated
behavior and central morphology. Postflight testing revealed (a) delayed onset of
body righting responses, (b) cardiac deceleration (bradycardia) to 70 degrees
head-up roll, (c) decreased branching of gravistatic afferent axons, but (d) no
change in branching of angular acceleration receptor projections with comparable
synaptogenesis of the medial vestibular nucleus in flight relative to control
fetuses. Kinematic analyses of the dams' on-orbit behavior suggest that, although
the fetal otolith organs are unloaded in microgravity, the fetus' semicircular
canals receive high levels of stimulation during longitudinal rotations of the
mother's weightless body. Behaviorally derived stimulation from maternal
movements may be a significant factor in studies of vestibular sensory
development. Taken together, these studies provide evidence that gravity and
angular acceleration shape prenatal organization and function within the
mammalian vestibular system. Copyright (c) 2008 APA, all rights reserved.
PMCID: PMC2610337
PMID: 18298265 [PubMed - indexed for MEDLINE]
56. J Clin Invest. 2008 Mar;118(3):1176-85.
Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects
in mice.
Nakano Y, Longo-Guess CM, Bergstrom DE, Nauseef WM, Jones SM, Bánfi B.
Department of Anatomy and Cell Biology, Inflammation Program, University of Iowa,
Iowa City, Iowa, USA.
In humans, hereditary inactivation of either p22(phox) or gp91(phox) leads to
chronic granulomatous disease (CGD), a severe immune disorder characterized by
the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of
p22(phox) and gp91(phox) proteins constitute the superoxide-producing cytochrome
core of the phagocyte NADPH oxidase. In this study, we identified the nmf333
mouse strain as what we believe to be the first animal model of p22(phox)
deficiency. Characterization of nmf333 mice revealed that deletion of p22(phox)
inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in
the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a
compound phenotype consisting of both a CGD-like immune defect and a balance
disorder caused by the aberrant development of gravity-sensing organs. Thus, in
addition to identifying a model of p22(phox)-dependent immune deficiency, our
study indicates that a clinically identifiable patient population with an
otherwise cryptic loss of gravity-sensor function may exist. Thus, p22(phox)
represents a shared and essential component of at least 2 superoxide-producing
cytochromes with entirely different biological functions. The site of p22(phox)
expression in the inner ear leads us to propose what we believe to be a novel
mechanism for the control of vestibular organogenesis.
PMCID: PMC2248803
PMID: 18292807 [PubMed - indexed for MEDLINE]
57. IEEE Rev Biomed Eng. 2008 Jan 1;1:115-142.
Cochlear Implants:System Design, Integration and Evaluation.
Zeng FG, Rebscher S, Harrison WV, Sun X, Feng H.
Departments of Anatomy and Neurobiology, Biomedical Engineering, Cognitive
Sciences and Otolaryngology - Head and Neck Surgery, University of California,
364 Med Surg II, Irvine, CA 92697, USA ( fzeng@uci.edu ).
As the most successful neural prosthesis, cochlear implants have provided partial
hearing to more than 120,000 persons worldwide; half of which being pediatric
users who are able to develop nearly normal language. Biomedical engineers have
played a central role in the design, integration and evaluation of the cochlear
implant system, but the overall success is a result of collaborative work with
physiologists, psychologists, physicians, educators, and entrepreneurs. This
review presents broad yet in-depth academic and industrial perspectives on the
underlying research and ongoing development of cochlear implants. The
introduction accounts for major events and advances in cochlear implants,
including dynamic interplays among engineers, scientists, physicians, and policy
makers. The review takes a system approach to address critical issues from design
and specifications to integration and evaluation. First, the cochlear implant
system design and specifications are laid out. Second, the design goals,
principles, and methods of the subsystem components are identified from the
external speech processor and radio frequency transmission link to the internal
receiver, stimulator and electrode arrays. Third, system integration and
functional evaluation are presented with respect to safety, reliability, and
challenges facing the present and future cochlear implant designers and users.
Finally, issues beyond cochlear implants are discussed to address treatment
options for the entire spectrum of hearing impairment as well as to use the
cochlear implant as a model to design and evaluate other similar neural
prostheses such as vestibular and retinal implants.
PMCID: PMC2782849
PMID: 19946565 [PubMed]
58. J Assoc Res Otolaryngol. 2008 Mar;9(1):65-89. Epub 2007 Dec 22.
Sox2 and JAGGED1 expression in normal and drug-damaged adult mouse inner ear.
Oesterle EC, Campbell S, Taylor RR, Forge A, Hume CR.
Virginia Merrill Bloedel Hearing Research Center, Department of
Otolaryngology-Head and Neck Surgery, University of Washington, CHDD CD176, Box
357923, Seattle, WA 98195-7923, USA. oesterle@u.washington.edu
Inner ear hair cells detect environmental signals associated with hearing,
balance, and body orientation. In humans and other mammals, significant hair cell
loss leads to irreversible hearing and balance deficits, whereas hair cell loss
in nonmammalian vertebrates is repaired by the spontaneous generation of
replacement hair cells. Research in mammalian hair cell regeneration is hampered
by the lack of in vivo damage models for the adult mouse inner ear and the
paucity of cell-type-specific markers for non-sensory cells within the sensory
receptor epithelia. The present study delineates a protocol to drug damage the
adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol
to investigate Sox2 and Jagged1 expression in damaged inner ear sensory
epithelia. In other tissues, the transcription factor Sox2 and a ligand member of
the Notch signaling pathway, Jagged1, are involved in regenerative processes.
Both are involved in early inner ear development and are expressed in developing
support cells, but little is known about their expressions in the adult. We
describe a nonsurgical technique for inducing hair cell damage in adult mouse
organ of Corti by a single high-dose injection of the aminoglycoside kanamycin
followed by a single injection of the loop diuretic furosemide. This drug
combination causes the rapid death of outer hair cells throughout the cochlea.
Using immunocytochemical techniques, Sox2 is shown to be expressed specifically
in support cells in normal adult mouse inner ear and is not affected by drug
damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of
vestibular hair cells. Double-labeling experiments with Sox2 and calbindin
suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in
support cells in the adult ear and is not affected by drug damage. Sox2 and
Jagged1 may be involved in the maintenance of support cells in adult mouse inner
ear.
PMCID: PMC2536811
PMID: 18157569 [PubMed - indexed for MEDLINE]
59. J Neurosci. 2007 Dec 19;27(51):14078-88.
Auditory neurons make stereotyped wiring decisions before maturation of their
targets.
Koundakjian EJ, Appler JL, Goodrich LV.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115,
USA.
Cochlear ganglion neurons communicate sound information from cochlear hair cells
to auditory brainstem neurons through precisely wired circuits. Understanding
auditory circuit assembly is a significant challenge because of the small size of
the otic vesicle and difficulties labeling and imaging embryonic neurons. We used
genetic fate mapping in the mouse to visualize the morphologies of individual
cochlear ganglion neurons throughout development, from their origin in the
Neurogenin1-positive neurogenic domain in the otic vesicle to the formation of
connections with targets in the cochlea and in the cochlear nucleus. We found
that auditory neurons with different patterns of connectivity arise from discrete
populations of Neurogenin1-positive precursors that make stereotyped wiring
decisions depending on when and where they are born. Auditory precursors are
segregated from vestibular precursors early in neurogenesis. Within this
population, cochlear ganglion neurons with type I and type II morphologies are
apparent before birth and develop within common pools of precursors. The
peripheral projections are initially complex and branched and then become simple
and straight after reaching the edge of the sensory epithelium. Subsequently, a
small number of projections attain obvious type II morphologies, beginning at
embryonic day 16.5 (E16.5), when hair cells begin to differentiate. Centrally,
cochlear ganglion axons are topographically organized in the auditory brainstem
as early as E15.5, when the cochlear nucleus is still immature. These findings
suggest that Neurogenin1 precursors possess intrinsic programs of differentiation
that direct early auditory circuit assembly events before the maturation of
presynaptic and postsynaptic target cells.
PMID: 18094247 [PubMed - indexed for MEDLINE]
60. Development. 2007 Dec;134(24):4405-15.
Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and
sensory hair cells during inner ear development.
Raft S, Koundakjian EJ, Quinones H, Jayasena CS, Goodrich LV, Johnson JE, Segil
N, Groves AK.
Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 West
3rd Street, Los Angeles CA 90057, USA.
Temporal and spatial coordination of multiple cell fate decisions is essential
for proper organogenesis. Here, we define gene interactions that transform the
neurogenic epithelium of the developing inner ear into specialized mechanosensory
receptors. By Cre-loxP fate mapping, we show that vestibular sensory hair cells
derive from a previously neurogenic region of the inner ear. The related bHLH
genes Ngn1 (Neurog1) and Math1 (Atoh1) are required, respectively, for neural and
sensory epithelial development in this system. Our analysis of mouse mutants
indicates that a mutual antagonism between Ngn1 and Math1 regulates the
transition from neurogenesis to sensory cell production during ear development.
Furthermore, we provide evidence that the transition to sensory cell production
involves distinct autoregulatory behaviors of Ngn1 (negative) and Math1
(positive). We propose that Ngn1, as well as promoting neurogenesis, maintains an
uncommitted progenitor cell population through Notch-mediated lateral inhibition,
and Math1 irreversibly commits these progenitors to a hair-cell fate.
PMID: 18039969 [PubMed - indexed for MEDLINE]
61. Int J Dev Biol. 2007;51(6-7):585-95.
Pocket proteins and cell cycle regulation in inner ear development.
Rocha-Sanchez SM, Beisel KW.
Creighton University School of Dentistry, Dept of Oral Biology, Omaha, NE 68178,
USA. ssanchez@creighton.edu
Loss of neurosensory cells of the ear, caused by genetic and non-genetic factors,
is becoming an increasing problem as people age, resulting in deafness and
vestibular disorders. Unveiling useful mechanisms of cell cycle regulation may
offer the possibility to generate new cells out of remaining ones, thus providing
the cellular basis to induce new hair cell differentiation in the mammalian ear.
Here, we provide an overview of cell cycle regulating genes in general and of
those studied in the ear in particular. We categorize those genes into regulators
that act upstream of the pocket proteins and into those that act downstream of
the pocket proteins. The three members of the pocket protein family essentially
determine, through interaction with the eight members of the E2F family, whether
or not the cell cycle will progress to the S-phase and thus cell division. The
abundant presence of one or more members of these families in adult hair cells
supports the notion that inhibition of cell cycle progression through these
proteins is a lifelong process. Indeed, manipulating some of those proteins,
unfortunately, leads to abortive entry into the cell cycle. Combined with recent
success to induce hair cell differentiation through molecular therapy, these
approaches may provide a viable strategy to restore lost hair cells in the inner
ear.
PMID: 17891719 [PubMed - indexed for MEDLINE]
62. Mamm Genome. 2007 Sep;18(9):646-56. Epub 2007 Sep 18.
Targeted knockout and lacZ reporter expression of the mouse Tmhs deafness gene
and characterization of the hscy-2J mutation.
Longo-Guess CM, Gagnon LH, Fritzsch B, Johnson KR.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
The Tmhs gene codes for a tetraspan transmembrane protein that is expressed in
hair cell stereocilia. We previously showed that a spontaneous missense mutation
of Tmhs underlies deafness and vestibular dysfunction in the hurry-scurry (hscy)
mouse. Subsequently, mutations in the human TMHS gene were shown to be
responsible for DFNB67, an autosomal recessive nonsyndromic deafness locus. Here
we describe a genetically engineered null mutation of the mouse Tmhs gene (Tmhs (
tm1Kjn )) and show that its phenotype is identical to that of the hscy missense
mutation, confirming the deleterious nature of the hscy cysteine-to-phenylalanine
substitution. In the targeted null allele, the Tmhs promoter drives expression of
a lacZ reporter gene. Visualization of beta-galactosidase activity in Tmhs (
tm1Kjn ) heterozygous mice indicates that Tmhs is highly expressed in the
cochlear and vestibular hair cells of the inner ear. Expression is first
detectable at E15.5, peaks around P0, decreases slightly at P6, and is absent by
P15, a duration that supports the involvement of Tmhs in stereocilia development.
Tmhs reporter gene expression also was detected in several cranial and cervical
sensory ganglia, but not in the vestibular or spiral ganglia. We also describe a
new nontargeted mutation of the Tmhs gene, hscy-2J, that causes abnormal splicing
from a cryptic splice site within exon 2 and is predicted to produce a
functionally null protein lacking 51 amino acids of the wild-type sequence.
PMCID: PMC2613174
PMID: 17876667 [PubMed - indexed for MEDLINE]
63. Development. 2007 Oct;134(20):3615-25. Epub 2007 Sep 12.
Fgf3 is required for dorsal patterning and morphogenesis of the inner ear
epithelium.
Hatch EP, Noyes CA, Wang X, Wright TJ, Mansour SL.
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112-5330,
USA.
The inner ear, which contains sensory organs specialized for hearing and balance,
develops from an ectodermal placode that invaginates lateral to hindbrain
rhombomeres (r) 5-6 to form the otic vesicle. Under the influence of signals from
intra- and extraotic sources, the vesicle is molecularly patterned and undergoes
morphogenesis and cell-type differentiation to acquire its distinct functional
compartments. We show in mouse that Fgf3, which is expressed in the hindbrain
from otic induction through endolymphatic duct outgrowth, and in the prospective
neurosensory domain of the otic epithelium as morphogenesis initiates, is
required for both auditory and vestibular function. We provide new morphologic
data on otic dysmorphogenesis in Fgf3 mutants, which show a range of
malformations similar to those of Mafb (Kreisler), Hoxa1 and Gbx2 mutants, the
most common phenotype being failure of endolymphatic duct and common crus
formation, accompanied by epithelial dilatation and reduced cochlear coiling. The
malformations have close parallels with those seen in hearing-impaired patients.
The morphologic data, together with an analysis of changes in the molecular
patterning of Fgf3 mutant otic vesicles, and comparisons with other mutations
affecting otic morphogenesis, allow placement of Fgf3 between hindbrain-expressed
Hoxa1 and Mafb, and otic vesicle-expressed Gbx2, in the genetic cascade initiated
by WNT signaling that leads to dorsal otic patterning and endolymphatic duct
formation. Finally, we show that Fgf3 prevents ventral expansion of r5-6
neurectodermal Wnt3a, serving to focus inductive WNT signals on the dorsal otic
vesicle and highlighting a new example of cross-talk between the two signaling
systems.
PMCID: PMC2366212
PMID: 17855431 [PubMed - indexed for MEDLINE]
64. Dev Biol. 2007 Oct 15;310(2):329-40. Epub 2007 Aug 9.
In vivo genetic ablation of the periotic mesoderm affects cell proliferation
survival and differentiation in the cochlea.
Xu H, Chen L, Baldini A.
Institute of Biosciences and Technology, Texas A&M Health Science Center,
Houston, TX 77030, USA.
Tbx1 is required for ear development in humans and mice. Gene manipulation in the
mouse has discovered multiple consequences of loss of function on early
development of the inner ear, some of which are attributable to a cell autonomous
role in maintaining cell proliferation of epithelial progenitors of the cochlear
and vestibular apparata. However, ablation of the mesodermal domain of the gene
also results in severe but more restricted abnormalities. Here we show that Tbx1
has a dynamic expression during late development of the ear, in particular, is
expressed in the sensory epithelium of the vestibular organs but not of the
cochlea. Vice versa, it is expressed in the condensed mesenchyme that surrounds
the cochlea but not in the one that surrounds the vestibule. Loss of Tbx1 in the
mesoderm disrupts this peri-cochlear capsule by strongly reducing the
proliferation of mesenchymal cells. The organogenesis of the cochlea, which
normally occurs inside the capsule, was dramatically affected in terms of growth
of the organ, as well as proliferation, differentiation and survival of its
epithelial cells. This model provides a striking demonstration of the essential
role played by the periotic mesenchyme in the organogenesis of the cochlea.
PMCID: PMC2223065
PMID: 17825816 [PubMed - indexed for MEDLINE]
65. Psychosom Med. 2007 Sep-Oct;69(7):700-7. Epub 2007 Aug 31.
Predicting continued dizziness after an acute peripheral vestibular disorder.
Heinrichs N, Edler C, Eskens S, Mielczarek MM, Moschner C.
Institute of Psychology, Technical University of Braunschweig, Spielmannstr. 12a,
38106 Braunschweig, Germany. n.heinrichs@tu-bs.de
OBJECTIVE: To identify individuals at risk of developing ongoing dizziness 3
months after an acute peripheral vestibular disorder episode, which is usually
functionally compensated or even healed within a few weeks. METHODS: In a
prospective longitudinal study, we assessed fear of bodily sensations and
cognitions related to anxiety at the time of hospital admission and 3 months
later in 43 patients with an episode of vestibular neuritis (VN) or benign
paroxysmal positional vertigo (BPPV). All participants were assessed for mental
disorders using a structured clinical interview. RESULTS: Only the interaction
between fear of bodily sensations within the first 2 weeks after admission and
the type of vestibular disorder predicted the extent of dizzy complaints 3 months
later; this accounts for 21% of the variance in a multiple regression analysis.
Specifically, the prediction was valid only in patients with VN but not in
patients with BPPV. Further analysis demonstrated that the interaction was not
due to the peripheral vestibular disorder per se but rather determined by the
initial severity of dizziness, which was significantly different in BPPV and VN
patients. CONCLUSIONS: The present study demonstrates that, for the development
of persistent psychogenic dizziness after a peripheral vestibular disorder, the
fear of bodily sensations is only relevant in interaction with the initial
severity of dizziness experienced during the acute organic episode. To prevent
development of persistent psychogenic dizziness, we feel that our results
indicate the need to screen patients with vestibular disorders for at-risk status
and offer them psychological support to deal with their symptoms.
PMID: 17766688 [PubMed - indexed for MEDLINE]
66. J Neurosci. 2007 Aug 15;27(33):8940-51.
Dominant-negative inhibition of M-like potassium conductances in hair cells of
the mouse inner ear.
Holt JR, Stauffer EA, Abraham D, Géléoc GS.
Department of Neuroscience, University of Virginia, Charlottesville, Virginia
22908, USA. jeffholt@virginia.edu
Sensory hair cells of the inner ear express multiple physiologically defined
conductances, including mechanotransduction, Ca(2+), Na(+), and several distinct
K(+) conductances, all of which are critical for normal hearing and balance
function. Yet, the molecular underpinnings and their specific contributions to
sensory signaling in the inner ear remain obscure. We sought to identify
hair-cell conductances mediated by KCNQ4, which, when mutated, causes the
dominant progressive hearing loss DFNA2. We used the dominant-negative pore
mutation G285S and packaged the coding sequence of KCNQ4 into adenoviral vectors.
We transfected auditory and vestibular hair cells of organotypic cultures
generated from the postnatal mouse inner ear. Cochlear outer hair cells and
vestibular type I cells that expressed the transfection marker, green fluorescent
protein, and the dominant-negative KCNQ4 construct lacked the M-like conductances
that typify nontransfected control hair cells. As such, we conclude that the
M-like conductances in mouse auditory and vestibular hair cells can include KCNQ4
subunits and may also include KCNQ4 coassembly partners. To examine the function
of M-like conductances in hair cells, we recorded from cells transfected with
mutant KCNQ4 and injected transduction current waveforms in current-clamp mode.
Because the M-like conductances were active at rest, they contributed to the very
low potassium-selective input resistance, which in turn hyperpolarized the
resting potential and significantly attenuated the amplitude of the receptor
potential. Modulation of M-like conductances may allow hair cells the ability to
control the amplitude of their response to sensory stimuli.
PMCID: PMC2647843
PMID: 17699675 [PubMed - indexed for MEDLINE]
67. J Physiol. 2007 Sep 15;583(Pt 3):923-43. Epub 2007 Jul 12.
Developmental regulation of the membrane properties of central vestibular neurons
by sensory vestibular information in the mouse.
Eugène D, Deforges S, Guimont F, Idoux E, Vidal PP, Moore LE, Vibert N.
Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, UMR 7060,
CNRS-Université Paris Descartes, Paris. daniel.eugene@univ-paris5.fr
Comment in:
    J Physiol. 2007 Sep 15;583(Pt 3):815.
The effect of the lack of vestibular input on the membrane properties of central
vestibular neurons was studied by using a strain of transgenic,
vestibular-deficient mutant KCNE1(-/-) mice where the hair cells of the inner ear
degenerate just after birth. Despite the absence of sensory vestibular input,
their central vestibular pathways are intact. Juvenile and adult homozygous
mutant have a normal resting posture, but show a constant head bobbing behaviour
and display the shaker/waltzer phenotype characterized by rapid bilateral
circling during locomotion. In juvenile mice, the KCNE1 mutation was associated
with a strong decrease in the expression of the calcium-binding proteins
calbindin, calretinin and parvalbumin within the medial vestibular nucleus (MVN)
and important modifications of the membrane properties of MVN neurons. In adult
mice, however, there was almost no difference between the membrane properties of
MVN neurons of homozygous and control or heterozygous mutant mice, which have
normal inner ear hair cells and show no behavioural symptoms. The expression
levels of calbindin and calretinin were lower in adult homozygous mutant animals,
but the amount of calcium-binding proteins expressed in the MVN was much greater
than in juvenile mice. These data demonstrate that suppression of sensory
vestibular inputs during a 'sensitive period' around birth can generate the
circling/waltzing behaviour, but that this behaviour is not due to persistent
abnormalities of the membrane properties of central vestibular neurons.
Altogether, maturation of the membrane properties of central vestibular neurons
is delayed, but not impaired by the absence of sensory vestibular information.
PMCID: PMC2277192
PMID: 17627998 [PubMed - indexed for MEDLINE]
68. J Neurophysiol. 2007 Sep;98(3):1549-65. Epub 2007 Jul 11.
Activity of vestibular nuclei neurons during vestibular and optokinetic
stimulation in the alert mouse.
Beraneck M, Cullen KE.
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Mathieu.beraneck@univ-paris5.fr
As a result of the availability of genetic mutant strains and development of
noninvasive eye movements recording techniques, the mouse stands as a very
interesting model for bridging the gap among behavioral responses, neuronal
response dynamics studied in vivo, and cellular mechanisms investigated in vitro.
Here we characterized the responses of individual neurons in the mouse vestibular
nuclei during vestibular (horizontal whole body rotations) and full field visual
stimulation. The majority of neurons ( approximately 2/3) were sensitive to
vestibular stimulation but not to eye movements. During the vestibular-ocular
reflex (VOR), these neurons discharged in a manner comparable to the "vestibular
only" (VO) neurons that have been previously described in primates. The remaining
neurons [eye-movement-sensitive (ES) neurons] encoded both head-velocity and
eye-position information during the VOR. When vestibular and visual stimulation
were applied so that there was sensory conflict, the behavioral gain of the VOR
was reduced. In turn, the modulation of sensitivity of VO neurons remained
unaffected, whereas that of ES neurons was reduced. ES neurons were also
modulated in response to full field visual stimulation that evoked the
optokinetic reflex (OKR). Mouse VO neurons, however, unlike their primate
counterpart, were not modulated during OKR. Taken together, our results show that
the integration of visual and vestibular information in the mouse vestibular
nucleus is limited to a subpopulation of neurons which likely supports gaze
stabilization for both VOR and OKR.
PMID: 17625061 [PubMed - indexed for MEDLINE]
69. Gene Expr Patterns. 2007 Aug;7(7):798-807. Epub 2007 May 26.
Expression of LHX3 and SOX2 during mouse inner ear development.
Hume CR, Bratt DL, Oesterle EC.
Department of Otolaryngology - Head and Neck Surgery, Virginia Merrill Bloedel
Hearing Research Center, University of Washington, VMBHRC, CHDD, CD176, Box
357923, 1959 NE Pacific, Seattle, WA 98195, USA. hume@u.washington.edu
A cascade of transcription factors is believed to regulate the coordinate
differentiation of primordial inner ear cells into the subtypes of hair cells and
supporting cells. While candidate genes involved in this process have been
identified, the temporal and spatial patterns of expression of many of these have
not been carefully described during the extended period of inner ear development
and functional maturation. We systematically examined the expression of two such
transcription factors, LHX3 and SOX2, from the time of hair cell terminal mitoses
into adulthood. We show that LHX3 is expressed specifically in auditory and
vestibular hair cells soon after terminal mitoses and persists into the adult in
vestibular hair cells. While SOX2 expression is widespread in the inner ear
sensory epithelia prior to hair cell differentiation, it has a unique pattern of
expression in the mature auditory and vestibular organs.
PMCID: PMC2043117
PMID: 17604700 [PubMed - indexed for MEDLINE]
70. BMC Neurosci. 2007 Jun 18;8:40.
The development of descending projections from the brainstem to the spinal cord
in the fetal sheep.
Stockx EM, Anderson CR, Murphy SM, Cooke IR, Berger PJ.
Ritchie Centre for Baby Health Research, Monash Institute of Medical Research,
Monash University, Clayton, Victoria, Australia. elaine.stockx@med.monash.edu.au
BACKGROUND: Although the fetal sheep is a favoured model for studying the
ontogeny of physiological control systems, there are no descriptions of the
timing of arrival of the projections of supraspinal origin that regulate somatic
and visceral function. In the early development of birds and mammals, spontaneous
motor activity is generated within spinal circuits, but as development proceeds,
a distinct change occurs in spontaneous motor patterns that is dependent on the
presence of intact, descending inputs to the spinal cord. In the fetal sheep,
this change occurs at approximately 65 days gestation (G65), so we therefore
hypothesised that spinally-projecting axons from the neurons responsible for
transforming fetal behaviour must arrive at the spinal cord level shortly before
G65. Accordingly we aimed to identify the brainstem neurons that send projections
to the spinal cord in the mature sheep fetus at G140 (term = G147) with
retrograde tracing, and thus to establish whether any projections from the
brainstem were absent from the spinal cord at G55, an age prior to the marked
change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells
were found within and around nuclei in the reticular formation of the medulla and
pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus
of the solitary tract. This pattern of labelling is similar to that previously
reported in other species. The distribution of CTB labelled neurons in the G55
fetus was similar to that of the G140 fetus. CONCLUSION: The brainstem nuclei
that contain neurons which project axons to the spinal cord in the fetal sheep
are the same as in other mammalian species. All projections present in the mature
fetus at G140 have already arrived at the spinal cord by approximately one third
of the way through gestation. The demonstration that the neurons responsible for
transforming fetal behaviour in early ontogeny have already reached the spinal
cord by G55, an age well before the change in motor behaviour occurs, suggests
that the projections do not become fully functional until well after their
arrival at the spinal cord.
PMCID: PMC1919385
PMID: 17577416 [PubMed - indexed for MEDLINE]
71. J Vestib Res. 2006;16(4-5):179-86.
A critical period for the impact of vestibular sensation on ferret motor
development.
Van Cleave S, Shall MS.
Department of Physical Therapy, Virginia Commonwealth University, Richmond, VA
23298-0224, USA.
Children with hearing deficits and hypofunctioning vestibular receptors
frequently have delayed motor development. This study focuses on when the
vestibular system needs to be active for normal motor behavior development and
the maturation of the soleus muscle in the ferret. Both vestibular labyrinths
were removed from ferrets at Postnatal day 10 (P10), P21, or P45 and the
resulting data were compared with ferrets that had undergone a sham surgery at
the same ages. The animals were sacrificed at P120 (young adult ferret). The
resulting data from these ferrets revealed that standing and walking balance was
significantly affected when the vestibular system was eliminated at or before
P21. The soleus of P10 and P21 animals generally had smaller diameter muscle
fibers and proportionally less type I Myosin Heavy Chain (MHC) and more type IIX
MHC. The twitch contraction time of the soleus of the P21 group was significantly
slower than the other groups. It appears that the vestibular system is important
to motor and muscle fiber development in the ferret during the period before P21.
The eyes are still closed at that age and all of the vestibular receptors are not
fully mature. These findings imply a "critical period" for vestibular sensation
and the development of a muscle that is important to standing balance.
PMCID: PMC2034323
PMID: 17538206 [PubMed - indexed for MEDLINE]
72. Pain Physician. 2007 May;10(3):467-72.
Hydrocodone use and sensorineural hearing loss.
Ho T, Vrabec JT, Burton AW.
Baylor College of Medicine, Houston, TX, USA.
BACKGROUND: The hydrocodone/acetaminophen combination is one of the most commonly
used analgesic preparations. Isolated incidences of suspected association between
hydrocodone abuse and rapidly progressive hearing loss have been reported. In
this study, we describe the clinical characteristics of 5 patients presenting
with progressive hearing loss and a history of hydrocodone use. METHODS: Patients
presenting with rapidly progressive bilateral hearing loss who had a documented
history of hydrocodone use were selected for the study. The presentation,
audiologic findings, associated comorbidities, and treatment outcomes were
reviewed. RESULTS: All patients displayed rapidly progressive sensorineural
hearing loss without vestibular symptoms. Hearing loss was asymmetric in 3
patients at initial presentation, but progressed to profound loss, usually within
months. Steroid treatment has no effect on the progression of the hearing loss.
The admitted quantity of hydrocodone consumed ranged from 10 to 300 mg per day.
Hepatitis C was the most common comorbidity, present in 60% of the patients. All
patients underwent cochlear implantation with satisfactory results. CONCLUSIONS:
The chronic use of hydrocodone can be associated with progressive sensorineural
hearing loss. Successful auditory rehabilitation can be achieved with cochlear
implantation. Genetic polymorphisms of drug metabolizing enzymes as well as
associated comorbidities such as hepatitis C infection may be significant in the
development of hydrocodone ototoxicity, though additional investigations are
necessary.
PMID: 17525781 [PubMed - indexed for MEDLINE]
73. Braz J Otorhinolaryngol. 2007 Jan-Feb;73(1):100-5.
Otoneurologic findings in Type 1 Diabetes mellitus patients.
Rigon R, Rossi AG, Cóser PL.
Federal University of Santa Maria, Santa Maria, RS, Brazil. rafarigon@hotmail.com
Metabolic alterations, as they occur in Diabetes mellitus, have been mentioned in
the development and maintenance of complaints related to the vestibular and
auditory organs. AIM: To investigate the vestibular system in Type 1 Diabetic
mellitus population. MATERIAL AND METHOD: The present study was developed with 19
individuals, being 10 females (52.6%) and 9 males (47.3%), with ages varying from
8 to 25 years old, with medical diagnosis of Type 1 Diabetes mellitus. For result
comparison, a control group was selected with others 19 individuals, matching the
study group in age and gender. The evaluation protocol encompassed interview,
otoscopic inspection, dynamic and static balance evaluation, cerebellar tests and
vectoelectronystagmographic evaluation. STUDY DESIGN: Clinical prospective.
RESULTS: Alteration in the vectoelectronystagmographic evaluation were found in
36.84% (n=7) Type 1 Diabetes mellitus individuals, being 21.06% (n=4) Peripheral
Deficiency Vestibular Syndrome and 15.79% (n=3) Peripheral Irritative Vestibular
Syndrome. CONCLUSION: We conclude that Type 1 Diabetes mellitus individuals can
have their vestibular organ affected, even if there are no otoneurologic
complaints.
PMID: 17505607 [PubMed - indexed for MEDLINE]
74. Am J Hum Genet. 2007 Jun;80(6):1076-89. Epub 2007 Apr 24.
A mutation in CCDC50, a gene encoding an effector of epidermal growth
factor-mediated cell signaling, causes progressive hearing loss.
Modamio-Hoybjor S, Mencia A, Goodyear R, del Castillo I, Richardson G, Moreno F,
Moreno-Pelayo MA.
Unidad de Genetica Molecular, Hospital Ramon y Cajal, Madrid, Spain.
We previously mapped a novel autosomal dominant deafness locus, DFNA44, by
studying a family with postlingual, progressive, nonsyndromic hearing loss. We
report here on the identification of a mutation in CCDC50 as the cause of hearing
loss in the family. CCDC50 encodes Ymer, an effector of epidermal growth factor
(EGF)-mediated cell signaling that is ubiquitously expressed in different organs
and has been suggested to inhibit down-regulation of the EGF receptor. We have
examined its expression pattern in mouse inner ear. Western blotting and cell
transfection results indicate that Ymer is a soluble, cytoplasmic protein, and
immunostaining shows that Ymer is expressed in a complex spatiotemporal pattern
during inner ear development. In adult inner ear, the expression of Ymer is
restricted to the pillar cells of the cochlea, the stria vascularis, and the
vestibular sensory epithelia, where it shows spatial overlap with the
microtubule-based cytoskeleton. In dividing cells, Ymer colocalizes with
microtubules of the mitotic apparatus. We suggest that DFNA44 hearing loss may
result from a time-dependent disorganization of the microtubule-based
cytoskeleton in the pillar cells and stria vascularis of the adult auditory
system.
PMCID: PMC1867096
PMID: 17503326 [PubMed - indexed for MEDLINE]
75. Int J Dev Biol. 2007;51(3):201-9.
Cell proliferation during the early compartmentalization of the Xenopus laevis
inner ear.
Quick QA, Serrano EE.
Department of Biology, New Mexico State University, Las Cruces, New Mexico 88033,
USA.
The auditory and vestibular endorgans of the inner ear which are essential for
the senses of hearing and balance form early during development when the otocyst
undergoes a period of rapid growth and compartmentalization. Here we show the
spatial and temporal patterns of proliferating cells in the Xenopus laevis inner
ear as this organ develops from an otic vesicle at stage 31 until stage 47, an
age at which compartmentalization and the initial appearance of sensory
structures are evident. Sites of new cell production were identified in specimens
at stages 31, 37, 42, 45 and 47 using immunohistochemical methods to detect
bromodeoxyuridine (BrdU) incorporation three hours after exposure to this
thymidine analogue. Cells undergoing terminal mitosis at stages 37, 42 and 45
were detected by exposing specimens at these stages to BrdU and permitting
development to proceed until stage 47. Our results show that while newly
replicating cells are uniformly distributed throughout the stage 31 otic vesicle,
they are spatially restricted in stages 37 through 45, with few dividing cells
visible in the central patches of the emerging sensory epithelia. In contrast, no
clear proliferative pattern was discerned at stage 47. BrdU-positive cells that
had undergone terminal mitosis at stage 37, 42 and 45 were detected in the
central regions of nascent sensory epithelia at stage 47. These findings are
consistent with a developmental mechanism in which cells undergoing terminal
mitosis during early X. laevis stages contribute to sensory epithelia and in
which cell mixing and migration are features of inner ear compartmentalization.
PMID: 17486540 [PubMed - indexed for MEDLINE]
76. Development. 2007 May;134(9):1713-22. Epub 2007 Mar 29.
Opposing gradients of Gli repressor and activators mediate Shh signaling along
the dorsoventral axis of the inner ear.
Bok J, Dolson DK, Hill P, Rüther U, Epstein DJ, Wu DK.
National Institute on Deafness and Other Communication Disorders, Rockville, MD
20850, USA.
Organization of the vertebrate inner ear is mainly dependent on localized signals
from surrounding tissues. Previous studies demonstrated that sonic hedgehog (Shh)
secreted from the floor plate and notochord is required for specification of
ventral (auditory) and dorsal (vestibular) inner ear structures, yet it was not
clear how this signaling activity is propagated. To elucidate the molecular
mechanisms by which Shh regulates inner ear development, we examined embryos with
various combinations of mutant alleles for Shh, Gli2 and Gli3. Our study shows
that Gli3 repressor (R) is required for patterning dorsal inner ear structures,
whereas Gli activator (A) proteins are essential for ventral inner ear
structures. A proper balance of Gli3R and Gli2/3A is required along the length of
the dorsoventral axis of the inner ear to mediate graded levels of Shh signaling,
emanating from ventral midline tissues. Formation of the ventral-most otic
region, the distal cochlear duct, requires robust Gli2/3A function. By contrast,
the formation of the proximal cochlear duct and saccule, which requires less Shh
signaling, is achieved by antagonizing Gli3R. The dorsal vestibular region
requires the least amount of Shh signaling in order to generate the correct dose
of Gli3R required for the development of this otic region. Taken together, our
data suggest that reciprocal gradients of GliA and GliR mediate the responses to
Shh signaling along the dorsoventral axis of the inner ear.
PMID: 17395647 [PubMed - indexed for MEDLINE]
77. J Neurosci. 2007 Mar 21;27(12):3139-47.
Asymmetric distribution of prickle-like 2 reveals an early underlying
polarization of vestibular sensory epithelia in the inner ear.
Deans MR, Antic D, Suyama K, Scott MP, Axelrod JD, Goodrich LV.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115,
USA.
Vestibular hair cells have a distinct planar cell polarity (PCP) manifest in the
morphology of their stereocilia bundles and the asymmetric localization of their
kinocilia. In the utricle and saccule the hair cells are arranged in an orderly
array about an abrupt line of reversal that separates fields of cells with
opposite polarity. We report that the putative PCP protein Prickle-like 2 (Pk2)
is distributed in crescents on the medial sides of vestibular epithelial cells
before the morphological polarization of hair cells. Despite the presence of a
line of polarity reversal, crescent position is not altered between hair cells of
opposite polarity. Frizzled 6 (Fz6), a second PCP protein, is distributed
opposite Pk2 along the lateral side of vestibular support cells. Similar to Pk2,
the subcellular localization of Fz6 does not differ between cells located on
opposite sides of the line of reversal. In addition, in Looptail/Van Gogh-like2
mutant mice Pk2 is distributed asymmetrically at embryonic day 14.5 (E14.5), but
this localization is not coordinated between adjacent cells, and the crescents
subsequently are lost by E18.5. Together, these results support the idea that a
conserved PCP complex acts before stereocilia bundle development to provide an
underlying polarity to all cells in the vestibular epithelia and that cells on
either side of the line of reversal are programmed to direct the kinocilium in
opposite directions with respect to the polarity axis defined by PCP protein
distribution.
PMID: 17376975 [PubMed - indexed for MEDLINE]
78. J Physiol. 2007 Jun 15;581(Pt 3):1101-12. Epub 2007 Mar 1.
Developmental changes in potassium currents at the rat calyx of Held presynaptic
terminal.
Nakamura Y, Takahashi T.
Department of Neurophysiology, University of Tokyo Graduate School of Medicine,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
During early postnatal development, the calyx of Held synapse in the auditory
brainstem of rodents undergoes a variety of morphological and functional changes.
Among ionic channels expressed in the calyx, voltage-dependent K+ channels
regulate transmitter release by repolarizing the nerve terminal. Here we asked
whether voltage-dependent K+ channels in calyceal terminals undergo developmental
changes, and whether they contribute to functional maturation of this auditory
synapse. From postnatal day (P) 7 to P14, K+ currents became larger and faster in
activation kinetics, but did not change any further to P21. Likewise, presynaptic
action potentials became shorter in duration from P7 to P14 and remained stable
thereafter. The density of presynaptic K+ currents, assessed from excised patch
recording and whole-cell recordings with reduced [K+]i, increased by 2-3-fold
during the second postnatal week. Pharmacological isolation of K+ current
subtypes using tetraethylammonium (1 mM) and margatoxin (10 nM) revealed that the
density of Kv3 and Kv1 currents underwent a parallel increase, and their
activation kinetics became accelerated by 2-3-fold. In contrast, BK currents,
isolated using iberiotoxin (100 nM), showed no significant change during the
second postnatal week. Pharmacological block of Kv3 or Kv1 channels at P7 and P14
calyceal terminals indicated that the developmental changes of Kv3 channels
contribute to the establishment of reliable action potential generation at high
frequency, whereas those of Kv1 channels contribute to stabilizing the nerve
terminal. We conclude that developmental changes in K+ currents in the nerve
terminal contribute to maturation of high-fidelity fast synaptic transmission at
this auditory relay synapse.
PMCID: PMC2170855
PMID: 17331991 [PubMed - indexed for MEDLINE]
79. J Neurosci. 2007 Feb 28;27(9):2163-75.
A forward genetics screen in mice identifies recessive deafness traits and
reveals that pejvakin is essential for outer hair cell function.
Schwander M, Sczaniecka A, Grillet N, Bailey JS, Avenarius M, Najmabadi H, Steffy
BM, Federe GC, Lagler EA, Banan R, Hice R, Grabowski-Boase L, Keithley EM, Ryan
AF, Housley GD, Wiltshire T, Smith RJ, Tarantino LM, Müller U.
Department of Cell Biology, Institute for Childhood and Neglected Disease, The
Scripps Research Institute, La Jolla, California 92037, USA.
Deafness is the most common form of sensory impairment in the human population
and is frequently caused by recessive mutations. To obtain animal models for
recessive forms of deafness and to identify genes that control the development
and function of the auditory sense organs, we performed a forward genetics screen
in mice. We identified 13 mouse lines with defects in auditory function and six
lines with auditory and vestibular defects. We mapped several of the affected
genetic loci and identified point mutations in four genes. Interestingly, all
identified genes are expressed in mechanosensory hair cells and required for
their function. One mutation maps to the pejvakin gene, which encodes a new
member of the gasdermin protein family. Previous studies have described two
missense mutations in the human pejvakin gene that cause nonsyndromic recessive
deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the
pejvakin allele described here introduces a premature stop codon, causes outer
hair cell defects, and leads to progressive hearing loss. We also identified a
novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted
with progressive hearing loss. Our findings suggest that the mechanisms of
pathogenesis associated with pejvakin mutations are more diverse than previously
appreciated. More generally, our findings demonstrate that recessive screens in
mice are powerful tools for identifying genes that control the development and
function of mechanosensory hair cells and cause deafness in humans, as well as
generating animal models for disease.
PMID: 17329413 [PubMed - indexed for MEDLINE]
80. Arch Otolaryngol Head Neck Surg. 2007 Feb;133(2):162-8.
The influence of mutations in the SLC26A4 gene on the temporal bone in a
population with enlarged vestibular aqueduct.
Madden C, Halsted M, Meinzen-Derr J, Bardo D, Boston M, Arjmand E, Nishimura C,
Yang T, Benton C, Das V, Smith R, Choo D, Greinwald J.
Department of Audiovestibular Medicine, Manchester Royal Infirmary, Manchester,
England.
Erratum in:
    Arch Otolaryngol Head Neck Surg. 2007 Jun;133(6):607.
OBJECTIVE: To correlate genetic and audiometric findings with a detailed
radiologic analysis of the temporal bone in patients with enlarged vestibular
aqueduct (EVA) to ascertain the contribution of SLC26A4 gene mutations to this
phenotype. DESIGN: A retrospective review of patients with EVA identified in a
database of pediatric hearing-impaired patients. SETTING: A tertiary care
pediatric referral center. PATIENTS: Seventy-one children with EVA and screening
results for SLC26A4 mutations. MAIN OUTCOME MEASURES: Genetic screening results,
audiometric thresholds, and radiographic temporal bone measurements. RESULTS:
Seventy-one children with EVA were screened for SLC26A4 mutations. Mutations were
found in 27% of children overall, while only 8% had biallelic mutations. The mean
initial pure-tone average (PTA) was 59 dB; the mean final PTA was 67 dB. A
bilateral EVA was found in 48 (67%) of the children; a unilateral EVA was found
in 23 (33%). Progressive hearing loss (in at least 1 ear) was seen in 29 (41%) of
the patients. The strongest genotype-phenotype interaction was seen in children
with a bilateral EVA. Among children with SLC26A4 mutations, there was a
significantly wider vestibular aqueduct at the midpoint and a wider vestibule
width (P < .05) than in children without the mutation. Among patients with a
bilateral EVA, children with any SLC26A4 mutation were more likely to have a more
severe final PTA (64 dB vs 32 dB), larger midpoint measurement (2.1 vs 1.1 mm),
and larger operculum measurement (3.0 vs 2.0 mm) than those without the mutation
in their better-hearing ear (P < .05). CONCLUSIONS: In a population of pediatric
patients with an EVA and hearing loss, SLC26A4 mutations are a contributor to the
phenotype. Our data suggest that other genetic factors also have important
contributions to this phenotype. The presence of an abnormal SLC26A4 allele, even
in the heterozygous state, was associated with greater enlargement of the
vestibular aqueduct, abnormal development of the vestibule, and possibly a stable
hearing outcome.
PMID: 17309986 [PubMed - indexed for MEDLINE]
81. Sheng Li Xue Bao. 2007 Feb 25;59(1):71-8.
Changes of amino acid concentrations in the rat medial vestibular nucleus
following unilateral labyrinthectomy.
Yu HL, An Y, Jiang HY, Jin QH, Jin YZ.
Department of Pharmacology, Yanbian University College of Medicine, Yanji 133000,
China.
To understand the neurochemical mechanisms underlying the vestibular
compensation, we determined the levels of amino acids such as aspartate,
glutamate, glutamine, glycine, taurine, alanine in the medial vestibular nucleus
(MVN) following unilateral labyrinthectomy (UL), by using in vivo brain
microdialysis and high-performance liquid chromatography technique. Rats were
pretreated by infusing 2% lidocaine 1.2 mL or 10 mg arsanilic acid into the
tympanic cavity to obstruct uni-periphery vestibular organ, and then the levels
of amino acids were determined in MVN of normal control and ipsilateral or
contralateral lesional (ipsi-/contra-lesional) rats. In the control experiment,
the levels of aspartate, glutamate, glutamine, glycine, taurine, and alanine were
(6.15 +/- 0.59), (18.13 +/- 1.21), (33.73 +/- 1.67), (9.26 +/- 0.65), (9.56 +/-
0.77) and (10.07 +/- 0.83) pmol/8 muL sample, respectively. The concentrations of
aspartate and glutamate decreased, while the concentration of taurine increased
in the ipsi-lesional MVN of rats 10 min after infusing 2% lidocaine into middle
ear to obstruct uni-periphery vestibular organ. Whereas the concentration of
glutamate increased, the concentrations of glycine and alanine decreased in the
contra-lesional MVN, accompanied by imbalances of glutamate, glycine and alanine
in the bilateral nuclei. In contrast, the levels of glutamate and alanine
decreased, the level of glutamine increased in the ipsi-lesional MVN, and the
level of glutamate decreased in the contra-lesional MVN of rats 2 weeks after
infusing 10 mg arsanilic acid into the tympanic cavity to obstruct uni-periphery
vestibular organ. Furthermore, the level of glutamine in the ipsi-lesional MVN
was obviously higher than that in the contra-lesional MVN. These results
demonstrate that an imbalance of different amino acids appeared in bilateral MVN
after UL, and this imbalance decreased after the development of vestibular
compensation. Whereas the imbalance of glutamine release in bilateral nuclei
appeared after vestibular compensation.
PMID: 17294045 [PubMed - in process]
82. Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2997-3002. Epub 2007 Feb 9.
Differentiation of ES cells into cerebellar neurons.
Salero E, Hatten ME.
Laboratory of Developmental Neurobiology, The Rockefeller University, 1230 York
Avenue, New York, NY 10021-6399, USA.
The neuronal circuits of the cerebellar cortex are essential for motor and
sensory learning, associative memory formation, and the vestibular ocular reflex.
In children and young adults, tumors of the granule cell, the medulloblastomas,
represent 40% of brain tumors. We report the differentiation of E14 ES cells into
mature granule neurons by sequential treatment with secreted factors (WNT1, FGF8,
and RA) that initiate patterning in the cerebellar region of the neural tube,
bone morphogenic proteins (BMP6/7 and GDF7) that induce early granule cell
progenitor markers (MATH1, MEIS1, ZIC1), mitogens (SHH, JAG1) that control
proliferation and induce additional granule cell markers (Cyclin D2, PAX2/6), and
culture in glial-conditioned medium to induce markers of mature granule neurons
(GABAalpha(6)r), including ZIC2, a unique marker for granule neurons.
Differentiated ES cells formed classic "T-shaped" granule cell axons in vitro,
and implantation of differentiated Pde1c-Egfp-BAC transgenic ES cells into the
external granule cell layer of neonatal mice resulted in the extension of
parallel fibers, migration across the molecular layer, incorporation into the
internal granule cell layer, and extension of short dendrites, typical of young
granule cells forming synaptic connections with afferent mossy fibers. These
results underscore the utility of treating ES cells with local, inductive signals
that regulate CNS neuronal development in vivo as a strategy for cell replacement
therapy of defined neuronal populations.
PMCID: PMC1796781
PMID: 17293457 [PubMed - indexed for MEDLINE]
83. Brain Res. 2007 Mar 30;1139:117-25. Epub 2007 Jan 8.
Developmental expression of Kcnq4 in vestibular neurons and neurosensory
epithelia.
Rocha-Sanchez SM, Morris KA, Kachar B, Nichols D, Fritzsch B, Beisel KW.
Department of Oral Biology, Creighton University School of Dentistry, 2500
California Plaza, Omaha, NE 68178, USA. ssanchez@creighton.edu
Sensory signal transduction of the inner ear afferent neurons and hair cells
(HCs) requires numerous ionic conductances. The KCNQ4 voltage-gated M-type
potassium channel is thought to set the resting membrane potential in cochlear
HCs. Here we describe the spatiotemporal expression patterns of Kcnq4 and the
associated alternative splice forms in the HCs of vestibular labyrinth. Whole
mount immunodetection, qualitative and quantitative RT-PCR were performed to
characterize the expression patterns of Kcnq4 transcripts and proteins. A
topographical expression and upregulation of Kcnq4 during development was
observed and indicated that Kcnq4 is not restricted to either a specific
vestibular structure or cell type, but is present in afferent calyxes, vestibular
ganglion neurons, and both type I and type II HCs. Of the four alternative splice
variants, Kcnq4_v1 transcripts were the predominant form in the HCs, while
Kcnq4_v3 was the major variant in the vestibular neurons. Differential
quantitative expression of Kcnq4_v1 and Kcnq4_v3 were respectively detected in
the striolar and extra-striolar regions of the utricle and saccule. Analysis of
gerbils and rats yielded results similar to those obtained in mice, suggesting
that the spatiotemporal expression pattern of Kcnq4 in the vestibular system is
conserved among rodents. Analyses of vestibular HCs of Bdnf conditional mutant
mice, which are devoid of any innervation, demonstrate that regulation of Kcnq4
expression in vestibular HCs is independent of innervation.
PMCID: PMC1858668
PMID: 17292869 [PubMed - indexed for MEDLINE]
84. J Neurosci. 2007 Feb 7;27(6):1474-8.
Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells
mainly via activation of S1P2.
Herr DR, Grillet N, Schwander M, Rivera R, Müller U, Chun J.
Department of Molecular Biology, Helen L. Dorris Institute for Neurological and
Psychiatric Disorders, La Jolla, California 92037, USA.
Hearing requires the transduction of vibrational forces by specialized epithelial
cells in the cochlea known as hair cells. The human ear contains a finite number
of terminally differentiated hair cells that, once lost by noise-induced damage
or toxic insult, can never be regenerated. We report here that sphingosine
1-phosphate (S1P) signaling, mainly via activation of its cognate receptor S1P2,
is required for the maintenance of vestibular and cochlear hair cells in vivo.
Two S1P receptors, S1P2 and S1P3, were found to be expressed in the cochlea by
reverse transcription-PCR and in situ hybridization. Mice that are null for both
these receptors uniformly display progressive cochlear and vestibular defects
with hair cell loss, resulting in complete deafness by 4 weeks of age and, with
complete penetrance, balance defects of increasing severity. This study reveals
the previously unknown role of S1P signaling in the maintenance of cochlear and
vestibular integrity and suggests a means for therapeutic intervention in
degenerative hearing loss.
PMID: 17287522 [PubMed - indexed for MEDLINE]
85. J Biol Chem. 2007 Apr 6;282(14):10690-6. Epub 2007 Feb 6.
Deafness and stria vascularis defects in S1P2 receptor-null mice.
Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington
D, Bolz SS, Friedman TB, Hla T, Proia RL.
Genetics of Development and Disease Branch, NIDDK, National Institutes of Health,
Bethesda, Maryland 20892-1821, USA.
The S1P(2) receptor is a member of a family of G protein-coupled receptors that
bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high
affinity. The receptor is widely expressed and linked to multiple G protein
signaling pathways, but its physiological function has remained elusive. Here we
have demonstrated that S1P(2) receptor expression is essential for proper
functioning of the auditory and vestibular systems. Auditory brainstem response
analysis revealed that S1P(2) receptor-null mice were deaf by one month of age.
These null mice exhibited multiple inner ear pathologies. However, some of the
earliest cellular lesions in the cochlea were found within the stria vascularis,
a barrier epithelium containing the primary vasculature of the inner ear. Between
2 and 4 weeks after birth, the basal and marginal epithelial cell barriers and
the capillary bed within the stria vascularis of the S1P(2) receptor-null mice
showed markedly disturbed structures. JTE013, an S1P(2) receptor-specific
antagonist, blocked the S1P-induced vasoconstriction of the spiral modiolar
artery, which supplies blood directly to the stria vascularis and protects its
capillary bed from high perfusion pressure. Vascular disturbance within the stria
vascularis is a potential mechanism that leads to deafness in the S1P(2)
receptor-null mice.
PMID: 17284444 [PubMed - indexed for MEDLINE]
86. Conf Proc IEEE Eng Med Biol Soc. 2005;7:7380-5.
Electrical stimulation to restore vestibular function development of a 3-d
vestibular prosthesis.
Della Santina C, Migliaccio A, Patel A.
Departments of Otolaryngology-Head & Neck Surgery and Biomedical Engineering,
Johns Hopkins School of Medicine, Baltimore, MD, USA.
Patients who fail to compensate for bilateral loss of vestibular sensory function
are disabled by disequilibrium and illusory movement of the visual field during
head movement. An implantable prosthesis that restores vestibular sensation could
significantly improve quality of life for these patients. To be effective, such a
device should encode head rotation in all 3 dimensions. We describe the
3-dimensional angular vestibulo-ocular reflex of normal chinchillas and
vestibular-deficient chinchillas undergoing functional electrical stimulation of
the vestibular nerve. We also describe the design and fabrication of a
head-mounted, 8 electrode vestibular prosthesis that encodes head movement in 3
dimensions.
PMCID: PMC2767263
PMID: 17281986 [PubMed - in process]
87. Mol Cell Neurosci. 2007 Mar;34(3):468-80. Epub 2007 Feb 2.
Novel regional and developmental NMDA receptor expression patterns uncovered in
NR2C subunit-beta-galactosidase knock-in mice.
Karavanova I, Vasudevan K, Cheng J, Buonanno A.
Section on Molecular Neurobiology, National Institute of Child Health and Human
Development, Bldg. 35, Room 2C-1000, 35 Lincoln Drive, National Institutes of
Health, Bethesda, MD 20892, USA.
NMDA receptor "knock-in" mice were generated by inserting the nuclear
beta-galactosidase reporter at the NR2C subunit translation initiation site.
Novel cell types and dynamic patterns of NR2C expression were identified using
these mice, which were unnoticed before because reagents that specifically
recognize NR2C-containing receptors are non-existent. We identified a transition
zone from NR2C-expressing neurons to astrocytes in an area connecting the
retrosplenial cortex and hippocampus. We demonstrate that NR2C is expressed in a
subset of S100beta-positive/GFAP-negative glial cells in the striatum, olfactory
bulb and cerebral cortex. We also demonstrate novel areas of neuronal expression
such as retrosplenial cortex, thalamus, pontine and vestibular nuclei. In
addition, we show that during cerebellar development NR2C is expressed in
transient caudal-rostral gradients and parasagittal bands in subsets of granule
cells residing in the internal granular layer, further demonstrating
heterogeneity of granule neurons. These results point to novel functions of
NR2C-containing NMDA receptors.
PMCID: PMC1855159
PMID: 17276696 [PubMed - indexed for MEDLINE]
88. Development. 2007 Feb;134(4):647-58.
Tissue/planar cell polarity in vertebrates: new insights and new questions.
Wang Y, Nathans J.
Department of Molecular Biology and Genetics, Howard Hughes Medical Institute,
Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ywang@mail.jhmi.edu
This review focuses on the tissue/planar cell polarity (PCP) pathway and its role
in generating spatial patterns in vertebrates. Current evidence suggests that PCP
integrates both global and local signals to orient diverse structures with
respect to the body axes. Interestingly, the system acts on both subcellular
structures, such as hair bundles in auditory and vestibular sensory neurons, and
multicellular structures, such as hair follicles. Recent work has shown that
intriguing connections exist between the PCP-based orienting system and
left-right asymmetry, as well as between the oriented cell movements required for
neural tube closure and tubulogenesis. Studies in mice, frogs and zebrafish have
revealed that similarities, as well as differences, exist between PCP in
Drosophila and vertebrates.
PMID: 17259302 [PubMed - indexed for MEDLINE]
89. J Neurosci. 2007 Jan 24;27(4):782-90.
Multiple mechanosensory modalities influence development of auditory function.
Horowitz SS, Tanyu LH, Simmons AM.
Department of Psychology, Brown University, Providence, Rhode Island 02912, USA.
Sensory development can be dependent on input from multiple modalities. During
metamorphic development, ranid frogs exhibit rapid reorganization of pathways
mediating auditory, vestibular, and lateral line modalities as the animal
transforms from an aquatic to an amphibious form. Here we show that neural
sensitivity to the underwater particle motion component of sound follows a
different developmental trajectory than that of the pressure component.
Throughout larval stages, cells in the medial vestibular nucleus show best
frequencies to particle motion in the range from 15 to 65 Hz, with displacement
thresholds of <10 mum. During metamorphic climax, best frequencies significantly
increase, and sensitivity to lower-frequency (<25 Hz) stimuli tends to decline.
These findings suggest that continued sensitivity to particle motion may
compensate for the considerable loss of sensitivity to pressure waves observed
during the developmental deaf period. Transport of a lipophilic dye from
peripheral end organs to the dorsal medulla shows that fibers from the saccule in
the inner ear and from the anterior lateral line both terminate in the medial
vestibular nucleus. Saccular projections remain stable across larval development,
whereas lateral line projections degenerate during metamorphic climax.
Sensitivity to particle motion may be based on multimodal input early in
development and on saccular input alone during the transition to amphibious life.
PMID: 17251417 [PubMed - indexed for MEDLINE]
90. J Anat. 2007 Jan;210(1):78-88.
Neurotrophin and Trk neurotrophin receptors in the inner ear of Salmo salar and
Salmo trutta.
Catania S, Germanà A, Cabo R, Ochoa-Erena FJ, Guerrera MC, Hannestad J, Represa
J, Vega JA.
Dipartimento di Morfologia, Biochimica, Fisiologia e Produzione Animale,
Università di Messina, Italy.
Neurotrophins (NTs) and their signal transducing Trk receptors play a critical
role in the development and maintenance of specific neuronal populations in the
nervous system of higher vertebrates. They are responsible for the innervation of
the inner ear cochlear and vestibular sensory epithelia. Neurotrophins and Trks
are also present in teleosts but their distribution in the inner ear is unknown.
Thus, in the present study, we used Western-blot analysis and
immunohistochemistry to investigate the expression and cell localization of both
NTs and Trk receptors in the inner ear of alevins of Salmo salar and Salmo
trutta. Western-blot analysis revealed the occurrence of brain-derived
neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor
(NGF), as well as all three Trk receptors, i.e. TrkA, TrkB and TrkC, the
estimated molecular weights of which were similar to those expected for mammals.
Specific immunoreactivity for neurotrophins was detected mainly in the sensory
epithelia. In particular, BDNF immunoreactivity was found in the maculae of the
utricle and saccule, whereas NT-3 immunoreactivity was present in the sensory
epithelium of the cristae ampullaris. As a rule the sensory epithelia of the
inner ear lacked immunoreactivity for Trks, thus excluding possible mechanisms of
autocrinia and/or paracrinia. By contrast, overlapping subpopulations of neurons
in the statoacoustic ganglion expressed TrkA (about 15%), TrkB (about 65%) and
TrkC (about 45%). The present results demonstrate that, as in mammals and birds,
the inner ear of teleosts expresses the components of the neurotrophin-Trk
system, but their roles remain to be elucidated.
PMCID: PMC2100255
PMID: 17229285 [PubMed - indexed for MEDLINE]
91. J Assoc Res Otolaryngol. 2007 Mar;8(1):18-31. Epub 2006 Dec 14.
Differential distribution of stem cells in the auditory and vestibular organs of
the inner ear.
Oshima K, Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Géléoc GS, Edge A,
Holt JR, Heller S.
Department of Otolaryngology-Head & Neck Surgery, Stanford University School of
Medicine, 801 Welch Road, Stanford, CA 94305-5739, USA.
The adult mammalian cochlea lacks regenerative capacity, which is the main reason
for the permanence of hearing loss. Vestibular organs, in contrast, replace a
small number of lost hair cells. The reason for this difference is unknown. In
this work we show isolation of sphere-forming stem cells from the early postnatal
organ of Corti, vestibular sensory epithelia, the spiral ganglion, and the stria
vascularis. Organ of Corti and vestibular sensory epithelial stem cells give rise
to cells that express multiple hair cell markers and express functional ion
channels reminiscent of nascent hair cells. Spiral ganglion stem cells display
features of neural stem cells and can give rise to neurons and glial cell types.
We found that the ability for sphere formation in the mouse cochlea decreases
about 100-fold during the second and third postnatal weeks; this decrease is
substantially faster than the reduction of stem cells in vestibular organs, which
maintain their stem cell population also at older ages. Coincidentally, the
relative expression of developmental and progenitor cell markers in the cochlea
decreases during the first 3 postnatal weeks, which is in sharp contrast to the
vestibular system, where expression of progenitor cell markers remains constant
or even increases during this period. Our findings indicate that the lack of
regenerative capacity in the adult mammalian cochlea is either a result of an
early postnatal loss of stem cells or diminishment of stem cell features of
maturing cochlear cells.
PMCID: PMC2538418
PMID: 17171473 [PubMed - indexed for MEDLINE]
92. Braz J Biol. 2006 Aug;66(3):907-17.
Notes on the biology of Trypoxylon (Trypargilum) opacum Brèthes (Hymenoptera;
Crabronidae) in Southern Brazil.
Buschini ML, Wolff LL.
Depto de Biologia, UNICENTRO, Guarapuava, PR, Brazil. isatunes@yahoo.com.br
The present study investigated the abundance, seasonality and various
life-history traits of Trypoxylon (Trypargilum) opacum. Using trap-nests, 320
nests of T. opacum were collected in the Parque Municipal das Araucárias in
Southern Brazil (25 degrees 23' 36" S and 51 degrees 27' 19" W) over a 3 year
period. Nesting was more frequent during the warm season. Nests consisted of a
linear series of 1 to 8 brood cells separated by mud partitions, usually followed
by an empty vestibular cell and final-closure mud plug. Brood cells were most
commonly provisioned with spiders of the family Araneidae. Sex-ratio was strongly
female biased, 3.4:1 females:males. Natural enemies attacking nests T. opacum
included chrysidids, ichneumonids, sarcophagids, bombyliids and ants.
PMID: 17119839 [PubMed - indexed for MEDLINE]
93. Dev Dyn. 2007 Jan;236(1):306-13.
Comparative analysis of Gata3 and Gata2 expression during chicken inner ear
development.
Lilleväli K, Haugas M, Pituello F, Salminen M.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
The inner ear is a complex sensory organ with hearing and balance functions.
Gata3 and Gata2 are expressed in the inner ear, and to gain more insight into
their roles in otic development, we made a detailed expression analysis in
chicken embryos. At early stages, their expression was highly overlapping. At
later stages, Gata2 expression became prominent in vestibular and cochlear
nonsensory epithelia. In contrast to Gata2, Gata3 was mainly expressed in the
developing sensory epithelia, reflecting the importance of this factor in the
sensory-neural development of the inner ear. While the later expression patterns
of both Gata3 and Gata2 were highly conserved between chicken and mouse,
important differences were observed especially with Gata3 during early otic
development, providing indications of divergent molecular control during placode
invagination in mice and chickens. We also found indications that the regulatory
hierarchy observed in mouse, where Gata3 is upstream of Gata2 and Fgf10, could be
conserved in chicken.
PMID: 17103399 [PubMed - indexed for MEDLINE]
94. J Assoc Res Otolaryngol. 2006 Dec;7(4):383-98. Epub 2006 Oct 31.
Electrophysiological validation of a human prototype auditory midbrain implant in
a guinea pig model.
Lenarz M, Lim HH, Patrick JF, Anderson DJ, Lenarz T.
Otorhinolaryngology Department, Medical University of Hannover, Hannover, Lower
Saxony 30625, Germany.
The auditory midbrain implant (AMI) is a new treatment for hearing restoration in
patients with neural deafness or surgically inaccessible cochleae who cannot
benefit from cochlear implants (CI). This includes neurofibromatosis type II
(NF2) patients who, due to development and/or removal of vestibular schwannomas,
usually experience complete damage of their auditory nerves. Although the
auditory brainstem implant (ABI) provides sound awareness and aids lip-reading
capabilities for these NF2 patients, it generally only achieves hearing
performance levels comparable with a single-channel CI. In collaboration with
Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which
is designed for electrical stimulation along the well-defined tonotopic gradient
of the inferior colliculus central nucleus (ICC). Considering that better speech
perception and hearing performance has been correlated with a greater number of
discriminable frequency channels of information available, the ability of the AMI
to effectively activate discrete frequency regions within the ICC may enable
better hearing performance than achieved by the ABI. Therefore, the goal of this
study was to investigate if our AMI array could achieve low-threshold,
frequency-specific activation within the ICC, and whether the levels for ICC
activation via AMI stimulation were within safe limits for human application. We
electrically stimulated different frequency regions within the ICC via the AMI
array and recorded the corresponding neural activity in the primary auditory
cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs.
Based on our results, AMI stimulation achieves lower thresholds and more
localized, frequency-specific activation than CI stimulation. Furthermore, AMI
stimulation achieves cortical activation with current levels that are within safe
limits for central nervous system stimulation. This study confirms that our AMI
design is sufficient for ensuring safe and effective activation of the ICC, and
warrants further studies to translate the AMI into clinical application.
PMCID: PMC2504634
PMID: 17075701 [PubMed - indexed for MEDLINE]
95. J Neurophysiol. 2007 Feb;97(2):1684-704. Epub 2006 Oct 25.
Developmental changes in two voltage-dependent sodium currents in utricular hair
cells.
Wooltorton JR, Gaboyard S, Hurley KM, Price SD, Garcia JL, Zhong M, Lysakowski A,
Eatock RA.
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
Two kinds of sodium current (I(Na)) have been separately reported in hair cells
of the immature rodent utricle, a vestibular organ. We show that rat utricular
hair cells express one or the other current depending on age (between postnatal
days 0 and 22, P0-P22), hair cell type (I, II, or immature), and epithelial zone
(striola vs. extrastriola). The properties of these two currents, or a mix, can
account for descriptions of I(Na) in hair cells from other reports. The patterns
of Na channel expression during development suggest a role in establishing the
distinct synapses of vestibular hair cells of different type and epithelial zone.
All type I hair cells expressed I(Na,1), a TTX-insensitive current with a very
negative voltage range of inactivation (midpoint: -94 mV). I(Na,2) was TTX
sensitive and had less negative voltage ranges of activation and inactivation
(inactivation midpoint: -72 mV). I(Na,1) dominated in the striola at all ages,
but current density fell by two-thirds after the first postnatal week. I(Na,2)
was expressed by 60% of hair cells in the extrastriola in the first week, then
disappeared. In the third week, all type I cells and about half of type II cells
had I(Na,1); the remaining cells lacked sodium current. I(Na,1) is probably
carried by Na(V)1.5 subunits based on biophysical and pharmacological properties,
mRNA expression, and immunoreactivity. Na(V)1.5 was also localized to calyx
endings on type I hair cells. Several TTX-sensitive subunits are candidates for
I(Na,2).
PMID: 17065252 [PubMed - indexed for MEDLINE]
96. J Neurosci. 2006 Oct 4;26(40):10253-69.
M-like K+ currents in type I hair cells and calyx afferent endings of the
developing rat utricle.
Hurley KM, Gaboyard S, Zhong M, Price SD, Wooltorton JR, Lysakowski A, Eatock RA.
The Bobby R. Alford Department of Otorhinolaryngology, Head and Neck Surgery,
Baylor College of Medicine, Houston, Texas 77030, USA.
Type I vestibular hair cells have large K+ currents that, like neuronal M
currents, activate negative to resting potential and are modulatable. In rodents,
these currents are acquired postnatally. In perforated-patch recordings from rat
utricular hair cells, immature hair cells [younger than postnatal day 7 (P7)] had
a steady-state K+ conductance (g(-30)) with a half-activation voltage (V1/2) of
-30 mV. The size and activation range did not change in maturing type II cells,
but, by P16, type I cells had added a K conductance that was on average fourfold
larger and activated much more negatively. This conductance may comprise two
components: g(-60) (V1/2 of -60 mV) and g(-80) (V1/2 of -80 mV). g(-80) washed
out during ruptured patch recordings and was blocked by a protein kinase
inhibitor. M currents can include contributions from KCNQ and
ether-a-go-go-related (erg) channels. KCNQ and erg channel blockers both affected
the K+ currents of type I cells, with KCNQ blockers being more potent at younger
than P7 and erg blockers more potent at older than P16. Single-cell reverse
transcription-PCR and immunocytochemistry showed expression of KCNQ and erg
subunits. We propose that KCNQ channels contribute to g(-30) and g(-60) and erg
subunits contribute to g(-80). Type I hair cells are contacted by calyceal
afferent endings. Recordings from dissociated calyces and afferent endings
revealed large K+ conductances, including a KCNQ conductance. Calyx endings were
strongly labeled by KCNQ4 and erg1 antisera. Thus, both hair cells and calyx
endings have large M-like K+ conductances with the potential to control the gain
of transmission.
PMID: 17021181 [PubMed - indexed for MEDLINE]
97. J Neurosci. 2006 Oct 4;26(40):10188-98.
The chloride intracellular channel protein CLIC5 is expressed at high levels in
hair cell stereocilia and is essential for normal inner ear function.
Gagnon LH, Longo-Guess CM, Berryman M, Shin JB, Saylor KW, Yu H, Gillespie PG,
Johnson KR.
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Although CLIC5 is a member of the chloride intracellular channel protein family,
its association with actin-based cytoskeletal structures suggests that it may
play an important role in their assembly or maintenance. Mice homozygous for a
new spontaneous recessive mutation of the Clic5 gene, named jitterbug (jbg),
exhibit impaired hearing and vestibular dysfunction. The jbg mutation is a 97 bp
intragenic deletion that causes skipping of exon 5, which creates a translational
frame shift and premature stop codon. Western blot and immunohistochemistry
results confirmed the predicted absence of CLIC5 protein in tissues of jbg/jbg
mutant mice. Histological analysis of mutant inner ears revealed dysmorphic
stereocilia and progressive hair cell degeneration. In wild-type mice,
CLIC5-specific immunofluorescence was detected in stereocilia of both cochlear
and vestibular hair cells and also along the apical surface of Kolliker's organ
during cochlear development. Refined immunolocalization in rat and chicken
vestibular hair cells showed that CLIC5 is limited to the basal region of the
hair bundle, similar to the known location of radixin. Radixin immunostaining
appeared reduced in hair bundles of jbg mutant mice. By mass spectrometry and
immunoblotting, CLIC5 was shown to be expressed at high levels in stereocilia of
the chicken utricle, in an approximate 1:1 molar ratio with radixin. These
results suggest that CLIC5 associates with radixin in hair cell stereocilia and
may help form or stabilize connections between the plasma membrane and the
filamentous actin core.
PMID: 17021174 [PubMed - indexed for MEDLINE]
98. Dev Dyn. 2006 Nov;235(11):3026-38.
Zebrafish pax5 regulates development of the utricular macula and vestibular
function.
Kwak SJ, Vemaraju S, Moorman SJ, Zeddies D, Popper AN, Riley BB.
Biology Department, Texas A&M University, College Station, Texas, USA.
The zebrafish otic vesicle initially forms with only two sensory epithelia, the
utricular and saccular maculae, which primarily mediate vestibular and auditory
function, respectively. Here, we test the role of pax5, which is preferentially
expressed in the utricular macula. Morpholino knockdown of pax5 disrupts
vestibular function but not hearing. Neurons of the statoacoustic ganglion (SAG)
develop normally. Utricular hair cells appear to form normally but a variable
number subsequently undergo apoptosis and are extruded from the otic vesicle.
Dendrites of the SAG persist in the utricle but become disorganized after hair
cell loss. Hair cells in the saccule develop and survive normally. Otic
expression of pax5 requires pax2a and fgf3, mutations in which cause vestibular
defects, albeit by distinct mechanisms. Thus, pax5 works in conjunction with fgf3
and pax2a to establish and/or maintain the utricular macula and is essential for
vestibular function. (c) 2006 Wiley-Liss, Inc.
PMID: 17013878 [PubMed - indexed for MEDLINE]
99. Development. 2006 Oct;133(19):3837-46.
Ephrin A/EphA controls the rostral turning polarity of a lateral commissural
tract in chick hindbrain.
Zhu Y, Guthrie S, Murakami F.
SORST, Japan Science and Technology, Japan. yan.zhu@fbs.osaka-u.ac.jp
Most post-crossing commissural axons turn into longitudinal paths to make
synaptic connections with their targets. Mechanisms that control their
rostrocaudal turning polarity are still poorly understood. We used the hindbrain
as a model system to investigate the rostral turning of a laterally located
commissural tract, identified as the caudal group of contralateral
cerebellar-projecting second-order vestibular neurons (cC-VC). We found that the
caudal hindbrain possessed a graded non-permissive/repulsive activity for growing
cC-VC axons. This non-permissiveness/repulsion was in part mediated by
glycosyl-phosphatidylinositol (GPI)-anchored ephrin A. We further demonstrated
that ephrin A2 was distributed in a caudal-high/rostral-low gradient in the
caudolateral hindbrain and cC-VC axons expressed EphA receptors. Finally,
perturbing ephrin A/EphA signalling both in vitro and in vivo led to rostrocaudal
pathfinding errors of post-crossing cC-VC axons. These results suggest that
ephrin A/EphA interactions play a key role in regulating the polarity of
post-crossing cC-VC axons as they turn into the longitudinal axis.
PMID: 16968816 [PubMed - indexed for MEDLINE]
100. J Med Genet. 2007 Feb;44(2):153-60. Epub 2006 Sep 8.
Development of a genotyping microarray for Usher syndrome.
Cremers FP, Kimberling WJ, Külm M, de Brouwer AP, van Wijk E, te Brinke H,
Cremers CW, Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley
PM, Haralambous E, Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy
BP, Silvestri G, McKay GJ, Koenekoop RK, Millan JM, Rosenberg T, Joensuu T,
Sankila EM, Weil D, Weston MD, Wissinger B, Kremer H.
Department of Human Genetics, and Nijmegen Centre for Molecular Life Sciences,
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
F.Cremers@antrg.umcn.nl
BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and
sensorineural hearing loss with or without vestibular dysfunction, displays a
high degree of clinical and genetic heterogeneity. Three clinical subtypes can be
distinguished, based on the age of onset and severity of the hearing impairment,
and the presence or absence of vestibular abnormalities. Thus far, eight genes
have been implicated in the syndrome, together comprising 347 protein-coding
exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we
developed a genotyping microarray based on the arrayed primer extension (APEX)
method. Allele-specific oligonucleotides corresponding to all 298 Usher
syndrome-associated sequence variants known to date, 76 of which are novel, were
arrayed. RESULTS: Approximately half of these variants were validated using
original patient DNAs, which yielded an accuracy of >98%. The efficiency of the
Usher genotyping microarray was tested using DNAs from 370 unrelated European and
American patients with Usher syndrome. Sequence variants were identified in
64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with
Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20
(30%) patients with atypical Usher syndrome. The chip also identified two novel
sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A.
CONCLUSION: The Usher genotyping microarray is a versatile and affordable
screening tool for Usher syndrome. Its efficiency will improve with the addition
of novel sequence variants with minimal extra costs, making it a very useful
first-pass screening tool.
PMCID: PMC2598068
PMID: 16963483 [PubMed - indexed for MEDLINE]

Revision as of 00:51, 11 June 2010

Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear. Deng M, Pan L, Xie X, Gan L. Dev Biol. 2010 Feb 1;338(1):38-49. Epub 2009 Nov 10. PMID: 19913004

Tbx1 and Brn4 regulate retinoic acid metabolic genes during cochlear morphogenesis. Braunstein EM, Monks DC, Aggarwal VS, Arnold JS, Morrow BE. BMC Dev Biol. 2009 May 29;9:31. PMID: 19476657

Semicircular canal size determines the developmental onset of angular vestibuloocular reflexes in larval Xenopus. Lambert FM, Beck JC, Baker R, Straka H. J Neurosci. 2008 Aug 6;28(32):8086-95. PMID: 18685033

Vestibular evoked myogenic potentials: past, present and future. Rosengren SM, Welgampola MS, Colebatch JG. Clin Neurophysiol. 2010 May;121(5):636-51. Epub 2010 Jan 18. Review. PMID: 20080441

Neurofibromatosis type 2 (NF2): a clinical and molecular review. Evans DG. Orphanet J Rare Dis. 2009 Jun 19;4:16. Review. PMID: 19545378

Development and assessment of the vestibular system. Nandi R, Luxon LM. Int J Audiol. 2008 Sep;47(9):566-77. Review. PMID: 18821226

http://informahealthcare.com/doi/abs/10.1080/14992020802324540

Surgery of the semicircular canals. Portmann D, Guindi S. Rev Laryngol Otol Rhinol (Bord). 2008;129(1):3-9. Review. PMID: 18777763 [


Vestibular Development

1. Pendred Syndrome/DFNB4.

Smith RJH, Van Camp G. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 1998 Sep 28.

Disease characteristics. Pendred syndrome and DFNB4 comprise a phenotypic spectrum of hearing loss with or without other findings. Pendred syndrome is characterized by severe-to-profound bilateral sensorineural hearing impairment that is usually congenital and non-progressive, vestibular dysfunction, temporal bone abnormalities, and development of euthyroid goiter in late childhood to early adulthood. Variability of findings is considerable, even within the same family. DFNB4 is characterized by nonsyndromic sensorineural hearing impairment, vestibular dysfunction, and temporal bone abnormalities. Thyroid defects are not seen in DFNB4. Diagnosis/testing. Pendred syndrome and DFNB4 are diagnosed clinically in individuals with (1) hearing impairment that is usually congenital and often severe to profound, although mild-to-moderate progressive hearing impairment also occurs; and (2) bilateral dilation of the vestibular aqueduct (DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear hypoplasia (the presence of both DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia). In addition, individuals with Pendred syndrome have either an abnormal perchlorate discharge test or goiter (when no other etiology of the goiter is evident and perchlorate washout cannot be performed). The only two genes known to be associated with Pendred syndrome/DFNB4 are SLC26A4 (~50% of affected individuals) and FOXI1 (~1% of affected individuals, suggesting further genetic heterogeneity). Sequence analysis identifies disease-causing mutations in approximately 50% of affected individuals from multiplex families and 20% of individuals from simplex families; such testing is clinically available. FOXI1 testing is available on a research basis only. Management. Treatment of manifestations: hearing habituation, hearing aids, and educational programs designed for the hearing impaired; consideration of cochlear implantation in individuals with severe-to-profound deafness. Standard treatment of abnormal thyroid function. Surveillance: semiannual or annual assessment of hearing and endocrine function. Repeat audiometry initially every three to six months if hearing loss is progressive. Agents/circumstances to avoid: weightlifting and contact sports. Genetic counseling. Pendred syndrome/DFNB4 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible when the family-specific mutations are known.

PMID: 20301640 [PubMed]


2. Dev Dyn. 2010 Apr;239(4):1102-12.

Long-term consequences of Sox9 depletion on inner ear development.

Park BY, Saint-Jeannet JP.

Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

The transcription factor Sox9 has been implicated in inner ear formation in several species. To investigate the long-term consequences of Sox9 depletion on inner ear development we analyzed the inner ear architecture of Sox9-depleted Xenopus tadpoles generated by injection of increasing amounts of Sox9 morpholino antisense oligonucleotides. We found that Sox9-depletion resulted in major defects in the development of vestibular structures, semicircular canals and utricle, while the ventrally located saccule was less severely affected in these embryos. Consistent with this phenotype, we observed a specific loss of the dorsal expression of Wnt3a expression in the otic vesicle of Sox9 morphants, associated with an increase in cell death and a reduction in cell proliferation in the region of the presumptive otic epithelium. We propose that, in addition to its early role in placode specification, Sox9 is also required for the maintenance of progenitors in the otic epithelium.

PMCID: PMC2847000 PMID: 20201105 [PubMed - in process]


3. PLoS One. 2010 Feb 23;5(2):e9377.

Canal cristae growth and fiber extension to the outer hair cells of the mouse ear require Prox1 activity.

Fritzsch B, Dillard M, Lavado A, Harvey NL, Jahan I.

Department of Biology, University of Iowa, Iowa City, Iowa, United States of America. bernd-fritzsch@uiowa.edu

BACKGROUND: The homeobox gene Prox1 is required for lens, retina, pancreas, liver, and lymphatic vasculature development and is expressed in inner ear supporting cells and neurons. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the role of Prox1 in the developing mouse ear taking advantage of available standard and conditional Prox1 mutant mouse strains using Tg(Pax2-Cre) and Tg(Nes-Cre). A severe reduction in the size of the canal cristae but not of other vestibular organs or the cochlea was identified in the E18.5 Prox1(Flox/Flox); Tg(Pax2-Cre) mutant ear. In these mutant embryos, hair cell differentiated; however, their distribution pattern was slightly disorganized in the cochlea where the growth of type II nerve fibers to outer hair cells along Prox1 expressing supporting cells was severely disrupted. In the case of Nestin-Cre, we found that newborn Prox1(Flox/Flox); Tg(Nestin-Cre) exhibit only a disorganized innervation of outer hair cells despite apparently normal cellular differentiation of the organ of Corti, suggesting a cell-autonomous function of Prox1 in neurons. CONCLUSIONS/SIGNIFICANCE: These results identify a dual role of Prox1 during inner ear development; growth of the canal cristae and fiber guidance of Type II fibers along supporting cells in the cochlea.

PMCID: PMC2826422 PMID: 20186345 [PubMed - in process]


4. Int J Otolaryngol. 2009;2009:972565. Epub 2010 Jan 27.

The importance of saccular function to motor development in children with hearing impairments.

Shall MS.

Department of Physical Therapy, Virginia Commonwealth University, P.O. Box 980224, Richmond, VA 23298-0224, USA.

Children with hearing deficits frequently have delayed motor development. The purpose of this study was to evaluate saccular function in children with hearing impairments using the Vestibular Evoked Myogenic Potential (VEMP). The impact of the saccular hypofunction on the timely maturation of normal balance strategies was examined using the Movement Assessment Battery for Children (Movement ABC). Thirty-three children with bilateral severe/profound hearing impairment between 4 and 7 years of age were recruited from a three-state area. Approximately half of the sample had one or bilateral cochlear implants, one used bilateral hearing aids, and the rest used no amplification. Parents reported whether the hearing impairment was diagnosed within the first year or after 2 years of age. No VEMP was evoked in two thirds of the hearing impaired (HI) children in response to the bone-conducted stimulus. Children who were reportedly hearing impaired since birth had significantly poorer scores when tested with the Movement ABC.

PMCID: PMC2817862 PMID: 20148080 [PubMed - in process]


5. J Rehabil Res Dev. 2009;46(6):797-810.

Auditory and vestibular dysfunction associated with blast-related traumatic brain injury.

Fausti SA, Wilmington DJ, Gallun FJ, Myers PJ, Henry JA.

Department of Veterans Affairs (VA) Rehabilitation Research and Development Service, National Center for Rehabilitative Auditory Research, Portland VA Medical Center, Portland, OR 97239, USA.

The dramatic escalation of blast exposure in military deployments has created an unprecedented amount of traumatic brain injury (TBI) and associated auditory impairment. Auditory dysfunction has become the most prevalent individual service-connected disability, with compensation totaling more than 1 billion dollars annually. Impairment due to blast can include peripheral hearing loss, central auditory processing deficits, vestibular impairment, and tinnitus. These deficits are particularly challenging in the TBI population, as symptoms can be mistaken for posttraumatic stress disorder, mental-health issues, and cognitive deficits. In addition, comorbid factors such as attention, cognition, neuronal loss, noise toxicity, etc., can confound assessment, causing misdiagnosis. Furthermore, some auditory impairments, such as sensorineural hearing loss, will continue to progress with age, unlike many other injuries. In the TBI population, significant clinical challenges are the accurate differentiation of auditory and vestibular impairments from multiple, many times overlapping, symptoms and the development of multidisciplinary rehabilitation strategies to improve treatment outcomes and quality of life for these patients.

PMID: 20104403 [PubMed - indexed for MEDLINE]


6. BMC Ear Nose Throat Disord. 2009 Dec 29;9:13.

An evaluation of the cost-effectiveness of booklet-based self-management of dizziness in primary care, with and without expert telephone support.

Yardley L, Kirby S, Barker F, Little P, Raftery J, King D, Morris A, Mullee M.

School of Psychology, University of Southampton, Highfield, Southampton, UK.

BACKGROUND: Dizziness is a very common symptom that often leads to reduced quality of life, anxiety and emotional distress, loss of fitness, lack of confidence in balance, unsteadiness and an increased risk of falling. Most dizzy patients are managed in primary care by reassurance and medication to suppress symptoms. Trials have shown that chronic dizziness can be treated effectively in primary care using a self-help booklet to teach patients vestibular rehabilitation exercises that promote neurological adaptation and skill and confidence in balance. However, brief support from a trained nurse was provided in these trials, and this model of managing dizzy patients has not been taken up due to a lack of skills and resources in primary care. The aim of this trial is to evaluate two new alternative models of delivery that may be more feasible and cost-effective. METHODS/DESIGN: In a single blind two-centre pragmatic controlled trial, we will randomise 330 patients from 30 practices to a) self-help booklet with telephone support from a vestibular therapist, b) self-help booklet alone, c) routine medical care. Symptoms, disability, handicap and quality of life will be assessed by validated questionnaires administered by post at baseline, immediately post-treatment (3 months), and at one year follow-up. The study is powered to test our primary hypothesis, that the self-help booklet with telephone support will be more effective than routine care. We will also explore the effectiveness of the booklet without any support, and calculate the costs of treatment in each arm. DISCUSSION: If our trial indicates that patients can cost-effectively manage their dizziness in primary care, then it can be easily rolled out to relieve the symptoms of the many patients in primary care who currently have chronic, untreated, disabling dizziness. Treatment in primary care may reduce the development of psychological and physical sequelae that cause handicap and require treatment. There is also the potential to reduce the cost to the NHS of treating dizziness by reducing demand for referral to secondary care for specialist assessment and treatment. TRIAL REGISTRATION: ClinicalTrials.gov trial registration ID number: NCT00732797.

PMCID: PMC2810289 PMID: 20098640 [PubMed - in process]


7. Cases J. 2009 Dec 21;2:9367.

Migraine vestibulopathy in three families with idiopathic scoliosis: a case series.

Uneri A, Polat S, Aydingoz O, Bursali A.

Department of Otorhinolaryngology, Balance Center, Acibadem Health Group Koztayagi Hospital, Istanbul, 34742, Turkey.

INTRODUCTION: We assessed clinical and etiological association between vestibular pathology and idiopathic scoliosis concerning seven members of three families with idiopathic scoliosis. CASE PRESENTATION: The families were referred to neurotology center for evaluation of balance problems. Patients were evaluated thorough anamnesis to relevant vestibular and audiological studies in addition to idiopathic scoliosis assessment. All evaluated scoliotic patients had clinical manifestations of vestibular dysfunctions and migrainous headache. All of the scoliotic patients (seven patients) in these three families were diagnosed as migraine vestibulopathy. CONCLUSION: With the presentation of these three families, we discussed the probable role of the vestibular dysfunctions including migraine vestibulopathy in the development and progression of idiopathic scoliosis.

PMCID: PMC2804012 PMID: 20062612 [PubMed - in process]


8. J Clin Sleep Med. 2009 Aug 15;5(4):374-5.

Association of idiopathic rapid eye movement sleep behavior disorder in an adult with persistent, childhood onset rhythmic movement disorder.

Xu Z, Anderson KN, Shneerson JM.

Westmead Hospital, Sydney, Australia.

We present a case of a 41-year-old man with the association of REM sleep behavior disorder (RBD) and rhythmic movement disorder (RMD). The RMD had a childhood onset and persisted into adulthood. The RMD worsened with the development of RBD and has persisted despite successful treatment of RBD. However, the pathogenesis of RMD remains unclear and the movements have been suggested to play a maturational role as part of psychomotor development by stimulating the vestibular apparatus. Current models underlying the control of REM sleep may need to be refined to explain the observed association of RBD and RMD.

PMCID: PMC2725259 PMID: 19968018 [PubMed - indexed for MEDLINE]


9. PLoS One. 2009 Nov 11;4(11):e7786.

Disorganized innervation and neuronal loss in the inner ear of Slitrk6-deficient mice.

Katayama K, Zine A, Ota M, Matsumoto Y, Inoue T, Fritzsch B, Aruga J.

Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.

Slitrks are type I transmembrane proteins that share conserved leucine-rich repeat domains similar to those in the secreted axonal guidance molecule Slit. They also show similarities to Ntrk neurotrophin receptors in their carboxy-termini, sharing a conserved tyrosine residue. Among 6 Slitrk family genes in mammals, Slitrk6 has a unique expression pattern, with strong expression in the sensory epithelia of the inner ear. We generated Slitrk6-knockout mice and investigated the development of their auditory and vestibular sensory organs. Slitrk6-deficient mice showed pronounced reduction in the cochlear innervation. In the vestibule, the innervation to the posterior crista was often lost, reduced, or sometimes misguided. These defects were accompanied by the loss of neurons in the spiral and vestibular ganglia. Cochlear sensory epithelia from Slitrk6-knockout mice have reduced ability in promoting neurite outgrowth of spiral ganglion neurons. Indeed the Slitrk6-deficient inner ear showed a mild but significant decrease in the expression of Bdnf and Ntf3, both of which are essential for the innervation and survival of sensory neurons. In addition, the expression of Ntrk receptors, including their phosphorylated forms was decreased in Slitrk6-knockout cochlea. These results suggest that Slitrk6 promotes innervation and survival of inner ear sensory neurons by regulating the expression of trophic and/or tropic factors including neurotrophins from sensory epithelia.

PMCID: PMC2777407 PMID: 19936227 [PubMed - indexed for MEDLINE]


10. Dev Biol. 2010 Feb 1;338(1):38-49. Epub 2009 Nov 10.

Requirement for Lmo4 in the vestibular morphogenesis of mouse inner ear.

Deng M, Pan L, Xie X, Gan L.

University of Rochester Flaum Eye Institute, University of Rochester, Rochester, NY 14642, USA.

During development, compartmentalization of an early embryonic structure produces blocks of cells with distinct properties and developmental potentials. The auditory and vestibular components of vertebrate inner ears are derived from defined compartments within the otocyst during embryogenesis. The vestibular apparatus, including three semicircular canals, saccule, utricle, and their associated sensory organs, detects angular and linear acceleration of the head and relays the information through vestibular neurons to vestibular nuclei in the brainstem. How the early developmental events manifest vestibular structures at the molecular level is largely unknown. Here, we show that LMO4, a LIM-domain-only transcriptional regulator, is required for the formation of semicircular canals and their associated sensory cristae. Targeted disruption of Lmo4 resulted in the dysmorphogenesis of the vestibule and in the absence of three semicircular canals, anterior and posterior cristae. In Lmo4-null otocysts, canal outpouches failed to form and cell proliferation was reduced in the dorsolateral region. Expression analysis of the known otic markers showed that Lmo4 is essential for the normal expression of Bmp4, Fgf10, Msx1, Isl1, Gata3, and Dlx5 in the dorsolateral domain of the otocyst, whereas the initial compartmentalization of the otocyst remains unaffected. Our results demonstrate that Lmo4 controls the development of the dorsolateral otocyst into semicircular canals and cristae through two distinct mechanisms: regulating the expression of otic specific genes and stimulating the proliferation of the dorsolateral part of the otocyst.

PMCID: PMC2812651 PMID: 19913004 [PubMed - indexed for MEDLINE]


11. Acta Otolaryngol. 2010 Apr;130(4):420-8.

The intravestibular source of the vestibular aqueduct. II: its structure and function clarified by a developmental study of the intra-skeletal channels of the otic capsule.

Michaels L, Soucek S, Linthicum F.

University College London Ear Institute and Department of Cellular Pathology, UCL Medical School, University Street, London. UK. l.michaels@ucl.ac.uk

CONCLUSION: A developmental histologic study of the otic capsule indicates that it grows a system of lamellar bone with abundant interconnecting intraosseous channels. These include the 'cartilage canals' in the cartilage model, the chondro-osseous and Haversian-like (Volkmann's) canals in the ossified otic capsule, the fissula ante fenestram, which seems to function as a lifelong manufacturer of the latter two channels, and the inner layer (vestibular arch) of the vestibular aqueduct, which is a complex series of Volkmann's canals and microcanals. Chemical changes, possibly produced by breakdown of cells within the channels, may provide a homeostatic environment for the functions of hearing and balance that take place in the endolymphatic fluid. OBJECTIVES: We studied the development of the otic capsule to clarify the cellular appearances that we had previously described in the normal vestibular arch and the changes in that structure in Ménière's disease. METHODS: Step sections from 84 temporal bones, including those from fetuses, children and adults from a variety of ages were examined histologically. RESULTS: Cartilage canals, bringing blood vessels and mesenchymal cells from perichondrium to the depths of the cartilage model to mediate ossification, are found early in fetal life and disappear when ossification is complete at about 24 weeks. The otic capsule is formed of chondro-osseous canals, which are composed of trabeculae of mineralized cartilage lacunae containing mesenchymal cells that undergo ossification (globuli ossei); also Volkmann's canals (like Haversian canals in long bones but multidirectional), which are produced from osteoblasts. The lumina of the latter frequently link up with chondro-osseous canals. Lamellar bone forms the background of the otic capsule. The fissula ante fenestram is present from early in the cartilage model and then throughout life. It appears to mediate bone production and the new formation of chondro-osseous channels and Volkmann's canals. The internal layer of the vestibular aqueduct (vestibular arch) is seen in the cartilage model of the otic capsule (present in early fetal life) as a vascular layer of perichondrally derived connective tissue (not cartilage) surrounding the endolymphatic duct. When endochondral ossification starts, the bone from the adjoining cochlear and vestibular sides embrace this connective tissue layer to form the outer bony layer of the vestibular aqueduct. Osteoblasts then fill the inner layer with lamellar bone and macro- and mini-Volkmann's canals. At 1 year osteoblasts in the walls of macro-Volkmann's canals, proliferating thereafter throughout life, produce large numbers of microcanals. It is possible that slow breakdown of these osteoblasts and of similar cells in the canals of the otic capsule proper may contribute to the homeostasis of the endolymphatic duct and that of the rest of the membranous labyrinth, respectively.

PMCID: PMC2865695 PMID: 19895329 [PubMed - in process]


12. Diagn Interv Radiol. 2009 Dec;15(4):239-41. Epub 2009 Oct 27.

Posttraumatic labyrinthitis ossificans with perilymphatic fistulization.

Aralaşmak A, Dinçer E, Arslan G, Cevikol C, Karaali K.

Department of Radiology, Akdeniz University School of Medicine, Antalya, Turkey. aysearalasmak@hotmail.com

Labyrinthitis ossificans is fibrosis or ossification of the membranous labyrinth. Tympanogenic, meningogenic, and hematogenous etiologies are more common than trauma in the development of labyrinthitis ossificans. We present a case complaining of right-sided hearing loss and symptoms of otitis media and positional vertigo resulting from perilymphatic fistulization. Imaging revealed labyrinthitis ossificans secondary to temporal bone fracture crossing through the otic capsule.

PMID: 19862674 [PubMed - indexed for MEDLINE]


13. Nan Fang Yi Ke Da Xue Xue Bao. 2009 Oct;29(10):2118-21.

[Cochlear implant in patients with congenital malformation of the inner ear]

[Article in Chinese]

Wan LC, Guo MH, Qian YH, Liu SX, Zhang HZ, Chen SJ, Chen H, Gong J.

Department of Otolaryngology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China. wanliangcai@126.com

OBJECTIVE: To summarize the clinical experience with multi-channel cochlear implantation in patients with inner ear malformations and evaluate and the outcomes of speech rehabilitation. METHODS: A retrospective study was conducted in 295 patients receiving cochlear implantation from 1998 to 2007, including 25 patients with large vestibular aqueduct syndrome (LVAS), 9 with Modini malformation, and 5 with common cavity deformity. All the patients received the Nucleus24 cochlear implants. In LVAS cases, 4 had Nucleus 24R (ST) implants, 8 had Contuor implants, 10 had Contuor Advance, and the remaining cases used Nucleus24(M) straight-electrode implants. RESULTS: Severe gusher appeared in 3 cases of LVAS, and perilymph fluctuation were seen in other 15 cases. Four patients with Mondini malformation and 2 with common cavity malformation also experienced severe gusher, but the electrodes were inserted smoothly in all the patients without postoperative facial paralysis or cerebrospinal fluid leakage. The hearing threshold in these patients was similar to that in patients with normal cochlear structure. After speech rehabilitation for over 6 months, the abilities of speech discrimination and spoken language improved in all the cases in comparison with the preoperative lingual functions. CONCLUSION: Multi-channel cochlear implantation can be performed in patients with inner ear malformation, but should not be attempted in patients with poor cochlear and cochlear nerve development. A comprehensive pre-operative radiographic and audiological evaluation is essential.

PMID: 19861281 [PubMed - in process]


14. Acta Otorrinolaringol Esp. 2009 Sep-Oct;60(5):318-24. Epub 2009 Jul 24.

[CSF fistulae following surgery for cerebellopontine angle tumours and their relationship with the body mass index]

[Article in Spanish]

Diaz Anadon A, Lassaletta L, Roda JM, Gavilán Bouzas J.

Servicio de Otorrinolaringología, Hospital Universitario La Paz, España. aguedadiazanadon@gmail.com

INTRODUCTION: The most frequent complication after vestibular schwannoma surgery is cerebrospinal fluid (CSF) fistula. MATERIAL AND METHODS: Retrospective study of 170 patients who had vestibular schwannoma (163) or other tumours in the cerebello pontine angle (CPA) (7). Resection was carried out using different approaches: retrosigmoid (66%), translabyrinthine (24%), middle cranial fossa (5%) and others (5%). We studied the day of onset, location and treatment of the CSF leaks, and the influence of demographic, radiological and clinical variables, including Body Mass Index. RESULTS: 27 patients developed a CSF fistula (15.9%): 15 were incisional (8.8%), 8 patients developed CSF rhinorrhea (4.7%), 1 CSF otorrhea (0.6%) and 3 a combination of the above (1.8%). We controlled 11 CSF fistulae with bed rest and compressive dressings (6.5%), 7 required lumbar drainage (4.1%), 2 lumbar drainage and wound closure with local anaesthesia (1.2%) and 7 patients required returning to the operating room under general anaesthesia (4.1%). There was not a significant relationship between the apparition of CSF and tumour size, type of approach, age or body mass index (BMI). CONCLUSIONS: Despite the great development and new surgical techniques, CSF fistulae are still a frequent complication after VS surgery. There might be other aetiological factors such as intracranial pressure. There was no significant relationship between CSF fistula and BMI. Adequate management and early conservative measures led to reduced reintervention rates of less than 5% in all patients.

PMID: 19814983 [PubMed - indexed for MEDLINE]


15. J Neurosci. 2009 Oct 7;29(40):12477-83.

Vestibular asymmetry as the cause of idiopathic scoliosis: a possible answer from Xenopus.

Lambert FM, Malinvaud D, Glaunès J, Bergot C, Straka H, Vidal PP.

Centre National de la Recherche Scientifique , Unité Mixte de Recherche 7060-Université Paris Descartes, 75006 Paris, France.

Human idiopathic scoliosis is characterized by severe deformations of the spine and skeleton. The occurrence of vestibular-related deficits in these patients is well established but it is unclear whether a vestibular pathology is the common cause for the scoliotic syndrome and the gaze/posture deficits or if the latter behavioral deficits are a consequence of the scoliotic deformations. A possible vestibular origin was tested in the frog Xenopus laevis by unilateral removal of the labyrinthine endorgans at larval stages. After metamorphosis into young adult frogs, X-ray images and three-dimensional reconstructed micro-computer tomographic scans of the skeleton showed deformations similar to those of scoliotic patients. The skeletal distortions consisted of a curvature of the spine in the frontal and sagittal plane, a transverse rotation along the body axis and substantial deformations of all vertebrae. In terrestrial vertebrates, the initial postural syndrome after unilateral labyrinthectomy recovers over time and requires body weight-supporting limb proprioceptive information. In an aquatic environment, however, this information is absent. Hence, the lesion-induced asymmetric activity in descending spinal pathways and the resulting asymmetric muscular tonus persists. As a consequence the mostly cartilaginous skeleton of the frog tadpoles progressively deforms. Lack of limb proprioceptive signals in an aquatic environment is thus the element, which links the Xenopus model with human scoliosis because a comparable situation occurs during gestation in utero. A permanently imbalanced activity in descending locomotor/posture control pathways might be the common origin for the observed structural and behavioral deficits in humans as in the different animal models of scoliosis.

PMID: 19812323 [PubMed - indexed for MEDLINE]


16. Theor Biol Med Model. 2009 Sep 1;6:19.

A model analysis of static stress in the vestibular membranes.

Pender DJ.

Department of Otolaryngology, Columbia University Medical Center New York, USA. djp2@columbia.edu

BACKGROUND: The scheme of the core vestibular membranes, consisting of serially connected utricle, ampulla and semicircular canal, first appeared hundreds of millions of years ago in primitive fish and has remained largely unchanged during the subsequent course of evolution. The labyrinths of higher organisms build on this core structure, with the addition of the phylogenetically newer membrane structures, namely, saccule, lagena and cochlea. An analysis of static stress in these core vestibular membranes may contribute to a better understanding of the role of stress in the evolution of derivative membrane structures over the long term as well as the short-term membrane distortions seen in Meniere's disease. METHODS: A model of these core vestibular membranes is proposed in order to analyze the distribution of stress in the walls of the component chambers. The model uses basic geometrical elements of hollow cylinders and spheres to emulate the actual structures. These model elements lend themselves to a mathematical analysis of static stress in their membranes. RESULTS: Hoop stress, akin to the stress in hoops used to reinforce barrel walls, is found to be the predominant stress in the model membranes. The level of hoop stress depends not only on pressure but as well on a geometric stress factor that incorporates membrane shape, thickness and curvature. This result implies that hoop stress may be unevenly distributed in the membranes of the several vestibular chambers due to variations in these dimensional parameters. These results provide a theoretical framework for appraising hoop stress levels in any vestibular labyrinth whose dimensions are known. CONCLUSION: Static hoop stress disparities are likely to exist in the vestibular membranes given their complex physical configurations. Such stress disparities may contribute to the development of membrane pathologies as seen in Meniere's Disease. They may also factor in the evolutionary development of other derivative membrane structures such as the saccule, the lagena, and the cochlea found in higher animals.

PMCID: PMC2745365 PMID: 19723316 [PubMed - indexed for MEDLINE]


17. J Neurosci. 2009 Aug 26;29(34):10779-83.

Long-term potentiation in the rat medial vestibular nuclei depends on locally synthesized 17beta-estradiol.

Grassi S, Frondaroli A, Dieni C, Scarduzio M, Pettorossi VE.

Department of Internal Medicine, Section of Human Physiology, University of Perugia, I-06126 Perugia, Italy. sgrassi@unipg.it

In male rat brainstem slices, we investigated the involvement of locally synthesized 17beta-estradiol (E(2)) in the induction in the medial vestibular nucleus (MVN) of long-term potentiation (LTP) by high-frequency stimulation (HFS) of the primary vestibular afferents. We demonstrated that the blockade of aromatase by letrozole or of E(2) receptors (ERalpha and ERbeta) by ICI 182,780 prevented the HFS-induced LTP of the N1 wave of the evoked field potential (FP) without affecting baseline responses. Only prolonged afferent activation could induce low LTP. In contrast, HFS applied under a combined blockade of GABA(A) receptors and aromatase or ERs was still able to induce LTP, but it was significantly lower and slower. These findings demonstrate that E(2) does not have a tonic influence on the activity of the MVN neurons and provide the first evidence of the crucial role played by local synthesis of E(2) in inducing LTP. We suggest that the synthesis of E(2) occurs after aromatase activation during HFS and facilitates the development of vestibular synaptic plasticity by influencing glutamate and GABA transmission.

PMID: 19710328 [PubMed - indexed for MEDLINE]


18. Tidsskr Nor Laegeforen. 2009 Aug 13;129(15):1469-73.

[Neurofibromatosis type 2 and auditory brainstem implantation]

[Article in Norwegian]

Elvsåshagen T, Solyga V, Bakke SJ, Heiberg A, Kerty E.

Avdeling for nevropsykiatri og psykosomatisk medisin, Nevroklinikken, Oslo universitetssykehus, Rikshospitalet 0027 Oslo og Institutt for psykiatri Det medisinske fakultet, Universitetet i Oslo, Norway. torbjorn.elvsashagen@rikshospitalet.no

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare and severe autosomal dominant disorder caused by mutations in a tumour suppressor gene. This article reviews NF2 and its treatment with auditory brainstem implantation. MATERIAL AND METHODS: The review is based on the authors' experience with the disease and literature identified through a non-systematic search of PubMed. RESULTS: NF2 is caused by loss-of-normal function of the tumour suppressor protein merlin. Merlin normally suppresses cell growth and proliferation. The clinical picture is dominated by neurological symptoms, caused by multiple tumours - mainly schwannomas and meningeomas. The hallmark of the disease is development of bilateral vestibular schwannomas, and the most common presenting symptom in adults is progressive hearing loss. Presenile cataract, ocular motility disorders, peripheral neuropathy and skin tumours are other common findings. The majority of patients become deaf, many patients become severely disabled and life expectancy is reduced. The goal of management is conservation of function and maintenance of quality of life. Auditory brainstem implants stimulate the cochlear nucleus directly and provide substantial auditory benefits to patients with NF2. INTERPRETATION: A multidisciplinary approach in specialty centres is recommended. Management by an experienced team reduces mortality and improves outcome after surgery. Auditory brainstem implantation is an important part of the hearing rehabilitation in these patients. Emerging knowledge of the molecular disease mechanisms offers hope for new therapeutic strategies.

PMID: 19690597 [PubMed - indexed for MEDLINE]


19. Development. 2009 Aug;136(16):2837-48.

Nkcc1 (Slc12a2) is required for the regulation of endolymph volume in the otic vesicle and swim bladder volume in the zebrafish larva.

Abbas L, Whitfield TT.

MRC Centre for Developmental and Biomedical Genetics and Department of Biomedical Science, University of Sheffield, Sheffield, UK.

Endolymph is the specialised extracellular fluid present inside the inner ear. In mammals, disruptions to endolymph homeostasis can result in either collapse or distension of the endolymphatic compartment in the cochlea, with concomitant hearing loss. The zebrafish little ears (lte) mutant shows a collapse of the otic vesicle in the larva, apparently owing to a loss of endolymphatic fluid in the ear, together with an over-inflation of the swim bladder. Mutant larvae display signs of abnormal vestibular function by circling and swimming upside down. The two available alleles of lte are homozygous lethal: mutant larvae fail to thrive beyond 6 days post-fertilisation. Patterning of the otic vesicle is apparently normal. However, the expression of several genes thought to play a role in endolymph production is downregulated, including the sodium-potassium-chloride cotransporter gene nkcc1 (slc12a2) and several Na(+)/K(+)-ATPase channel subunit genes. We show here that lte mutations correspond to lesions in nkcc1. Each allele has a point mutation that disrupts splicing, leading to frame shifts in the coding region that predict the generation of truncated products. Endolymph collapse in the lte/nkcc1 mutant shows distinct parallels to that seen in mouse Nkcc1 mutants, validating zebrafish as a model for the study of endolymph disorders. The collapse in ear volume can be ameliorated in the to27d allele of lte by injection of a morpholino that blocks splicing at an ectopic site introduced by the mutation. This exemplifies the use of morpholinos as potential therapeutic agents for genetic disease.

PMCID: PMC2730410 PMID: 19633174 [PubMed - indexed for MEDLINE]


20. Orphanet J Rare Dis. 2009 Jun 19;4:16.

Neurofibromatosis type 2 (NF2): a clinical and molecular review.

Evans DG.

Medical Genetics Research Group, Regional Genetics Service and National Molecular Genetics Reference Laboratory, Central Manchester Foundation Trust, St Mary's Hospital, Manchester M130JH, UK. dgr.evans@virgin.net

Neurofibromatosis type 2 (NF2) is a tumour-prone disorder characterised by the development of multiple schwannomas and meningiomas. Prevalence (initially estimated at 1: 200,000) is around 1 in 60,000. Affected individuals inevitably develop schwannomas, typically affecting both vestibular nerves and leading to hearing loss and deafness. The majority of patients present with hearing loss, which is usually unilateral at onset and may be accompanied or preceded by tinnitus. Vestibular schwannomas may also cause dizziness or imbalance as a first symptom. Nausea, vomiting or true vertigo are rare symptoms, except in late-stage disease. The other main tumours are schwannomas of the other cranial, spinal and peripheral nerves; meningiomas both intracranial (including optic nerve meningiomas) and intraspinal, and some low-grade central nervous system malignancies (ependymomas). Ophthalmic features are also prominent and include reduced visual acuity and cataract. About 70% of NF2 patients have skin tumours (intracutaneous plaque-like lesions or more deep-seated subcutaneous nodular tumours). Neurofibromatosis type 2 is a dominantly inherited tumour predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. More than 50% of patients represent new mutations and as many as one-third are mosaic for the underlying disease-causing mutation. Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common. A strategy for detection of the latter is vital for a sensitive analysis. Diagnosis is based on clinical and neuroimaging studies. Presymptomatic genetic testing is an integral part of the management of NF2 families. Prenatal diagnosis and pre-implantation genetic diagnosis is possible. The main differential diagnosis of NF2 is schwannomatosis. NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Surgery remains the focus of current management although watchful waiting with careful surveillance and occasionally radiation treatment have a role. Prognosis is adversely affected by early age at onset, a higher number of meningiomas and having a truncating mutation. In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating condition.

PMCID: PMC2708144 PMID: 19545378 [PubMed - indexed for MEDLINE]


21. J Korean Med Sci. 2009 May;24 Suppl 2:S258-66. Epub 2009 May 31.

Development of guideline for rating the physical impairment of otolaryngologic field.

Park CW, Do NY, Rha KS, Chung SM, Kwon YJ; Korean Academy of Medical Sciences.

Department of Otolaryngology, College of Medicine, Hanyang University, Seoul, Korea. cwpark@hanyang.ac.kr

We develop a guideline for rating the physical impairment of otolaryngologic fields. Assessment of hearing disturbance and tinnitus required physical examination, pure tone audiometry, speech audiometry, impedance audiometry, brainstem evoked response audiometry, Bekesy audiometry, otoacoustic emission test, and imaging examination. History taking, physical examination, and radiological examination for the vestibular organ and brain, righting reflex test, electronystagmography, and caloric test are taken for evaluation of balance disorder. Olfactory function tests include University of Pennsylvania Smell Identification test, Connecticut Chemosensory Clinical Research Center test, T and T olfactometry and Korean Version of Sniffin's Sticks test. Medical history and physical examination is mandatory to evaluatezseverity of respiration difficulty. Examinations include flexible fiberoptic nasopharyngoscope, bronchoscopy, simple soft-tissue radiography films of upper airway and high resolution computed tomography. Evaluation of mastication and swallowing are history taking, physical examination, examination for upper jaw, lower jaw, and temporomandibular joint, dental examination and radiological studies. Endoscopy and esophagography are also needed. Voice disorder is evaluated based on physical examination, oral pharynx and larynx endoscopy, larynx stroboscopy, hearing assessment, laryngeal electromyography, sound analysis test, aerodynamic test, electroglottography, and radiologic examination. Articulation disorder is assessed by picture consonant articulation test. These are position articulation test, Lee-Kim Korean articulation picture and speech intelligibility assessment.

PMCID: PMC2690073 PMID: 19503682 [PubMed - indexed for MEDLINE]


22. BMC Dev Biol. 2009 May 29;9:31.

Tbx1 and Brn4 regulate retinoic acid metabolic genes during cochlear morphogenesis.

Braunstein EM, Monks DC, Aggarwal VS, Arnold JS, Morrow BE.

Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. ebraunst@aecom.yu.edu

BACKGROUND: In vertebrates, the inner ear is comprised of the cochlea and vestibular system, which develop from the otic vesicle. This process is regulated via inductive interactions from surrounding tissues. Tbx1, the gene responsible for velo-cardio-facial syndrome/DiGeorge syndrome in humans, is required for ear development in mice. Tbx1 is expressed in the otic epithelium and adjacent periotic mesenchyme (POM), and both of these domains are required for inner ear formation. To study the function of Tbx1 in the POM, we have conditionally inactivated Tbx1 in the mesoderm while keeping expression in the otic vesicle intact. RESULTS: Conditional mutants (TCre-KO) displayed malformed inner ears, including a hypoplastic otic vesicle and a severely shortened cochlear duct, indicating that Tbx1 expression in the POM is necessary for proper inner ear formation. Expression of the mesenchyme marker Brn4 was also lost in the TCre-KO. Brn4-;Tbx1+/-embryos displayed defects in growth of the distal cochlea. To identify a potential signal from the POM to the otic epithelium, expression of retinoic acid (RA) catabolizing genes was examined in both mutants. Cyp26a1 expression was altered in the TCre-KO, while Cyp26c1 showed reduced expression in both TCre-KO and Brn4-;Tbx1+/- embryos. CONCLUSION: These results indicate that Tbx1 expression in the POM regulates cochlear outgrowth potentially via control of local retinoic acid activity.

PMCID: PMC2700094 PMID: 19476657 [PubMed - indexed for MEDLINE]


23. BMC Ear Nose Throat Disord. 2009 May 16;9:2.

Long-term symptoms in dizzy patients examined in a university clinic.

Wilhelmsen K, Ljunggren AE, Goplen F, Eide GE, Nordahl SH.

Department of Public Health and Primary Health Care, Section for Physiotherapy Science, University of Bergen, Bergen, Norway. Kjersti.Wilhelmsen@hib.no

BACKGROUND: The long-term course of dizziness was investigated combining medical chart and survey data. The survey was undertaken median (interquartile range (IQR)) 4.6 (4.3) years after the initial medical examination. METHODS: Chart data comprised sex, age, diagnosis, symptom duration, postural sway and neck pain. Survey data comprised symptom severity assessed by the Vertigo Symptom Scale - Short Form (VSS-SF), and data regarding current state of dizziness, medication, neck pain and other chronic conditions. RESULTS: The sample consisted of 503 patients, the mean (standard deviation (SD)) age was 50.0 (11.6) years, women being slightly overrepresented (60%). Severe problems with dizziness (VSS-SF mean (SD) 13.9, (10.8)) were indicated in the total group and in 5 of 6 diagnostic sub-groups. Vertigo/balance- and autonomic/anxiety-related symptoms were present in all groups. Current dizziness was confirmed by 73% who had significantly more severe problems than the non-dizzy (VSS-SF mean (SD): 17.2 (10.1) versus 5.0 (7.3)). Symptoms were related to vertigo/balance more than to autonomic/anxiety (test of interaction p < 0.001).Based on simple logistic regression analysis, sex, symptom duration, neck pain, sway and diagnoses predicted dizziness. Symptom duration and neck pain remained predictors in the adjusted analysis. Age, symptom duration, neck pain, sway and diagnoses predicted vertigo/balance-related dizziness in both regression analyses. Sex, neck pain and sway predicted development of autonomic/anxiety-related dizziness according to simple regression analysis, while only neck pain remained a significant predictor in the adjusted analysis. With respect to diagnosis, simple regression analysis showed significant reduced likelihood for development of dizziness in all vestibular sub-groups when compared to the non-otogenic dizziness group. With respect to vertigo/balance- and autonomic/anxiety-related symptoms, the implication of diagnostic belonging varied. No effect of diagnoses was seen in adjusted analyses. CONCLUSION: The majority of patients had persistent and severe problems with dizziness. The wait-and-see attitude before referral to specialist institutions may be questioned. Early, active movements seem necessary, and attention should be paid to the presence of neck pain. Diagnoses had limited prognostic value. Questionnaire-based evaluations could assist in classification and identification of type of dizziness and thereby provide a better basis for specific rehabilitation.

PMCID: PMC2693507 PMID: 19445693 [PubMed]


24. PLoS Genet. 2009 May;5(5):e1000480. Epub 2009 May 8.

Synaptojanin1 is required for temporal fidelity of synaptic transmission in hair cells.

Trapani JG, Obholzer N, Mo W, Brockerhoff SE, Nicolson T.

Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA.

To faithfully encode mechanosensory information, auditory/vestibular hair cells utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The molecular basis of SV release and consequent recycling of membrane in hair cells has not been fully explored. Here, we report that comet, a gene identified in an ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel activity but not mechanotransduction. Synaptojanin has been previously implicated in SV recycling; therefore, we tested synaptic transmission at hair-cell synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively normal spike rates when hair cells were mechanically stimulated for a short period of time at 20 Hz. In contrast, a sharp decline in the rate of firing occurred during prolonged stimulation at 20 Hz or stimulation at a higher frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were available for release. Consistent with this result, we observed that stimulated mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired phase locking of the postsynaptic activity to the mechanical stimulus. Following prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells displayed a striking delay in the recovery of spontaneous activity. Collectively, the data suggest that Synj1 is critical for retrieval of membrane in order to maintain the quantity, timing of fusion, and spontaneous release properties of SVs at hair-cell ribbon synapses.

PMCID: PMC2673039 PMID: 19424431 [PubMed - indexed for MEDLINE]


25. Acta Otorrinolaringol Esp. 2009 Mar-Apr;60(2):131-40.

[An update on the treatment of vestibular schwannoma]

[Article in Spanish]

Lassaletta L, Gavilán J.

Servicio de Otorrinolaringología, Hospital Universitario La Paz, Madrid, Spain. luikilassa@yahoo.com

The increase in the diagnosis of ever smaller vestibular schwannomas (VS), the fact that many tumours can be observed with serial MRI, and the development of radiosurgery as an alternative to microsurgery have led the neurotologic surgeon to a new global approach to patients with VS. On the other hand, the spread of internet-based information sources, often with biased or incomplete information, makes counselling patients with VS a challenging task. This study provides an overview of the natural history of these tumours and the main therapeutic options: observation, surgery and radiosurgery, with comments on their indications, advantages and disadvantages. Due to the completely different approach and peculiar features of bilateral VS in patients with type II neurofibromatosis, these are excluded.

PMID: 19401081 [PubMed - indexed for MEDLINE]


26. Dev Biol. 2009 Apr 15;328(2):285-96. Epub 2009 Feb 2.

Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.

Bosman EA, Quint E, Fuchs H, Hrabé de Angelis M, Steel KP.

The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

Large-scale mouse mutagenesis initiatives have provided new mouse mutants that are useful models of human deafness and vestibular dysfunction. Catweasel is a novel N-ethyl-N-nitrosourea (ENU)-induced mutation. Heterozygous catweasel mutant mice exhibit mild headtossing associated with a posterior crista defect. We mapped the catweasel mutation to a critical region of 13 Mb on chromosome 12 containing the Six1, -4 and -6 genes. We identified a basepair substitution in exon 1 of the Six1 gene that changes a conserved glutamic acid (E) at position 121 to a glycine (G) in the Six1 homeodomain. Cwe/Cwe animals lack Preyer and righting reflexes, display severe headshaking and have severely truncated cochlea and semicircular canals. Cwe/Cwe animals had very few hair cells in the utricle, but their ampullae and cochlea were devoid of any hair cells. Bmp4, Jag1 and Sox2 expression were largely absent at early stages of sensory development and NeuroD expression was reduced in the developing vestibulo-acoustic ganglion. Lastly we show that Six1 genetically interacts with Jag1. We propose that the catweasel phenotype is due to a hypomorphic mutation in Six1 and that catweasel mice are a suitable model for branchio-oto-renal syndrome. In addition Six1 has a pivotal role in early sensory patch development and may act in the same genetic pathway as Jag1.

PMCID: PMC2682643 PMID: 19389353 [PubMed - indexed for MEDLINE]


27. PLoS Genet. 2009 Apr;5(4):e1000455. Epub 2009 Apr 17.

Phoenix is required for mechanosensory hair cell regeneration in the zebrafish lateral line.

Behra M, Bradsher J, Sougrat R, Gallardo V, Allende ML, Burgess SM.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

In humans, the absence or irreversible loss of hair cells, the sensory mechanoreceptors in the cochlea, accounts for a large majority of acquired and congenital hearing disorders. In the auditory and vestibular neuroepithelia of the inner ear, hair cells are accompanied by another cell type called supporting cells. This second cell population has been described as having stem cell-like properties, allowing efficient hair cell replacement during embryonic and larval/fetal development of all vertebrates. However, mammals lose their regenerative capacity in most inner ear neuroepithelia in postnatal life. Remarkably, reptiles, birds, amphibians, and fish are different in that they can regenerate hair cells throughout their lifespan. The lateral line in amphibians and in fish is an additional sensory organ, which is used to detect water movements and is comprised of neuroepithelial patches, called neuromasts. These are similar in ultra-structure to the inner ear's neuroepithelia and they share the expression of various molecular markers. We examined the regeneration process in hair cells of the lateral line of zebrafish larvae carrying a retroviral integration in a previously uncharacterized gene, phoenix (pho). Phoenix mutant larvae develop normally and display a morphologically intact lateral line. However, after ablation of hair cells with copper or neomycin, their regeneration in pho mutants is severely impaired. We show that proliferation in the supporting cells is strongly decreased after damage to hair cells and correlates with the reduction of newly formed hair cells in the regenerating phoenix mutant neuromasts. The retroviral integration linked to the phenotype is in a novel gene with no known homologs showing high expression in neuromast supporting cells. Whereas its role during early development of the lateral line remains to be addressed, in later larval stages phoenix defines a new class of proteins implicated in hair cell regeneration.

PMCID: PMC2662414 PMID: 19381250 [PubMed - indexed for MEDLINE]


28. J Assoc Res Otolaryngol. 2009 Sep;10(3):321-40. Epub 2009 Apr 17.

Hes5 expression in the postnatal and adult mouse inner ear and the drug-damaged cochlea.

Hartman BH, Basak O, Nelson BR, Taylor V, Bermingham-McDonogh O, Reh TA.

Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.

The Notch signaling pathway is known to have multiple roles during development of the inner ear. Notch signaling activates transcription of Hes5, a homologue of Drosophila hairy and enhancer of split, which encodes a basic helix-loop-helix transcriptional repressor. Previous studies have shown that Hes5 is expressed in the cochlea during embryonic development, and loss of Hes5 leads to overproduction of auditory and vestibular hair cells. However, due to technical limitations and inconsistency between previous reports, the precise spatial and temporal pattern of Hes5 expression in the postnatal and adult inner ear has remained unclear. In this study, we use Hes5-GFP transgenic mice and in situ hybridization to report the expression pattern of Hes5 in the inner ear. We find that Hes5 is expressed in the developing auditory epithelium of the cochlea beginning at embryonic day 14.5 (E14.5), becomes restricted to a particular subset of cochlear supporting cells, is downregulated in the postnatal cochlea, and is not present in adults. In the vestibular system, we detect Hes5 in developing supporting cells as early as E12.5 and find that Hes5 expression is maintained in some adult vestibular supporting cells. In order to determine the effect of hair cell damage on Notch signaling in the cochlea, we damaged cochlear hair cells of adult Hes5-GFP mice in vivo using injection of kanamycin and furosemide. Although outer hair cells were killed in treated animals and supporting cells were still present after damage, supporting cells did not upregulate Hes5-GFP in the damaged cochlea. Therefore, absence of Notch-Hes5 signaling in the normal and damaged adult cochlea is correlated with lack of regeneration potential, while its presence in the neonatal cochlea and adult vestibular epithelia is associated with greater capacity for plasticity or regeneration in these tissues; which suggests that this pathway may be involved in regulating regenerative potential.

PMCID: PMC2757554 PMID: 19373512 [PubMed - indexed for MEDLINE]


29. BMC Neurosci. 2009 Mar 25;10:27.

Proteomic and functional analysis of NCS-1 binding proteins reveals novel signaling pathways required for inner ear development in zebrafish.

Petko JA, Kabbani N, Frey C, Woll M, Hickey K, Craig M, Canfield VA, Levenson R.

Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey PA 17033, USA. jac554@psu.edu

BACKGROUND: The semicircular canals, a subdivision of the vestibular system of the vertebrate inner ear, function as sensors of angular acceleration. Little is currently known, however, regarding the underlying molecular mechanisms that govern the development of this intricate structure. Zebrafish represent a particularly tractable model system for the study of inner ear development. This is because the ear can be easily visualized during early embryogenesis, and both forward and reverse genetic techniques are available that can be applied to the discovery of novel genes that contribute to proper ear development. We have previously shown that in zebrafish, the calcium sensing molecule neuronal calcium sensor-1 (NCS-1) is required for semicircular canal formation. The function of NCS-1 in regulating semicircular canal formation has not yet been elucidated. RESULTS: We initiated a multistep functional proteomic strategy to identify neuronal calcium sensor-1 (NCS-1) binding partners (NBPs) that contribute to inner ear development in zebrafish. By performing a Y2H screen in combination with literature and database searches, we identified 10 human NBPs. BLAST searches of the zebrafish EST and genomic databases allowed us to clone zebrafish orthologs of each of the human NBPs. By investigating the expression profiles of zebrafish NBP mRNAs, we identified seven that were expressed in the developing inner ear and overlapped with the ncs-1a expression profile. GST pulldown experiments confirmed that selected NBPs interacted with NCS-1, while morpholino-mediated knockdown experiments demonstrated an essential role for arf1, pi4kbeta, dan, and pink1 in semicircular canal formation. CONCLUSION: Based on their functional profiles, the hypothesis is presented that Ncs-1a/Pi4kbeta/Arf1 form a signaling pathway that regulates secretion of molecular components, including Dan and Bmp4, that are required for development of the vestibular apparatus. A second set of NBPs, consisting of Pink1, Hint2, and Slc25a25, are destined for localization in mitochondria. Our findings reveal a novel signalling pathway involved in development of the semicircular canal system, and suggest a previously unrecognized role for NCS-1 in mitochondrial function via its association with several mitochondrial proteins.

PMCID: PMC2679751 PMID: 19320994 [PubMed - indexed for MEDLINE]


30. Acta Otorrinolaringol Esp. 2009 Jan-Feb;60(1):49-53.

[Contribution of the vestibular evoked myogenic potentials to the study of the vestibular neuritis]

[Article in Spanish]

Lesmas Navarro MJ, Pérez Garrigues H, Morera Pérez C, Piqueras A.

Servicio de Otorrinolaringología, Hospital Universitario La Fe, Valencia, España.

INTRODUCTION: Until recently, the only tests available to provide information about vestibular function were caloric and kinetic tests, which only give us information about the external semicircular canal and the superior vestibular nerve. In recent years the development of vestibular evoked myogenic potentials has allowed us to assess the saccule and the inferior vestibular nerve. Our aim is, by studying the caloric test results as well as the vestibular evoked myogenic potentials in patients with Vestibular Neuritis, to determine whether they have involvement of the superior, inferior or both vestibular nerves. MATERIAL AND METHODS: Retrospective study of 9 patients with Vestibular Neuritis admitted to a tertiary care hospital. We studied them by means of anamnesis, otoneurological clinical examination, caloric test and vestibular evoked myogenic potentials. Their clinical progress after admission and any residual instability were also studied. RESULTS: Women were more affected (66.6 %) than males. The mean age for presentation of the disease was 53.8 +/- 14.0 years. Hospital stays lasted for 5.7 +/- 3.2 days. After their crises, they suffered from instability for 122 +/- 114 days. Four cases were diagnosed as Complete Vestibular Neuritis and five as Superior Vestibular Neuritis. P13 wave latency was normal in all cases. There were no differences between the groups in terms of the length of hospital stay nor residual instability. CONCLUSIONS: Nowadays, vestibular evoked myogenic potentials make it possible to advance further in the study of Vestibular Neuritis. Complete and superior vestibular neuritis are much more frequent than inferior vestibular neuritis. Clinical behaviour is similar in the sub-types found.

PMID: 19268130 [PubMed - indexed for MEDLINE]


31. Med Oral Patol Oral Cir Bucal. 2009 Mar 1;14(3):E146-52.

A descriptive study of 113 unerupted supernumerary teeth in 79 pediatric patients in Barcelona.

Ferrés-Padró E, Prats-Armengol J, Ferrés-Amat E.

Service of Oral and Maxillofacial Surgery, Hospital de Nens de Barcelona, Barcelona, Spain.

Unerupted supernumerary teeth, depending on the morphology, number and distribution can give rise to various alterations in the eruption and development of those permanent teeth to which they are related. OBJECTIVES: We aimed to make an epidemiological and descriptive study of the clinical characteristics of patients in Barcelona, their surgical treatment and how said treatment was hindered. MATERIALS AND METHODS: A descriptive study including 113 supernumerary teeth from 79 healthy pediatric patients between 5 and 19 years of age, which underwent surgery in our hospital during a 2 year period (May 2005 / May 2007), taking into account the variables of personal data, gender, age, location, number, morphology, position-axis, radiological study, surgical treatment, related pathologies, and surgical complications. RESULTS: Male patients (51) were more frequently affected than female (28) patients mainly within the central incisors-mesiodens (53.16%), in which the unique form (68.52%) predominates in conoid morphology (69.62%). Surgical treatment was done by palatal/lingual extraction (49.37%), with few surgical complications (only 1 case of post-surgical bleeding). CONCLUSION: Incidence in supernumerary teeth is higher among male patients (ratio M:F of 1.82:1). They are most frequently located in the maxilla (82%), specifically, in the premaxilla (77%). Most cases presented only one supernumerary tooth (68.5%) and, in multiple cases, the premolar region is predominant. The conoid shape is the commonest morphology (69.62%). Surgical extraction, was done by palatal/lingual in 49.37% of the cases, as opposed to the vestibular approach in 45.57%.

PMID: 19242396 [PubMed - indexed for MEDLINE]


32. J Exp Biol. 2009 Mar;212(Pt 5):639-47.

Plasma membrane calcium ATPase required for semicircular canal formation and otolith growth in the zebrafish inner ear.

Cruz S, Shiao JC, Liao BK, Huang CJ, Hwang PP.

Institute of Fisheries Science, College of Life Science, National Taiwan University, Taipei, Taiwan.

Fish otoliths consist of >90% calcium carbonate, the accretion of which depends on acellular endolymph. This study confirms the presence of plasma membrane calcium ATPase 1a isoform (Atp2b1a) in the auditory and vestibular system of a teleost fish. As shown by in situ hybridization, zebrafish atp2b1a is expressed mainly in larval otic placode and lateral-line neuromast as well as in the hair cells within the adult zebrafish inner ear chamber. Zebrafish atp2b1a knockdown by antisense morpholinos reduced the number of hair cells and produced malformation of semicircular canals and smaller otoliths. These defects coincide with unbalanced body orientation. The formation of smaller otoliths in atp2b1a morphants may stem from an impairment of calcium supply in the endolymph. However, otolith formation persists in most morphants, suggesting that other zebrafish Atp2b isoforms or paracellular pathways may also transport calcium into the endolymph. These results suggest that Atp2b1a plays an important role for normal development of the auditory and vestibular system as well as calcium transport in the inner ear of zebrafish.

PMID: 19218514 [PubMed - indexed for MEDLINE]


33. PLoS One. 2009;4(2):e4368. Epub 2009 Feb 3.

A late role for bmp2b in the morphogenesis of semicircular canal ducts in the zebrafish inner ear.

Hammond KL, Loynes HE, Mowbray C, Runke G, Hammerschmidt M, Mullins MC, Hildreth V, Chaudhry B, Whitfield TT.

MRC Centre for Developmental and Biomedical Genetics and Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.

BACKGROUND: The Bone Morphogenetic Protein (BMP) genes bmp2 and bmp4 are expressed in highly conserved patterns in the developing vertebrate inner ear. It has, however, proved difficult to elucidate the function of BMPs during ear development as mutations in these genes cause early embryonic lethality. Previous studies using conditional approaches in mouse and chicken have shown that Bmp4 has a role in semicircular canal and crista development, but there is currently no direct evidence for the role of Bmp2 in the developing inner ear. METHODOLOGY/PRINCIPAL FINDINGS: We have used an RNA rescue strategy to test the role of bmp2b in the zebrafish inner ear directly. Injection of bmp2b or smad5 mRNA into homozygous mutant swirl (bmp2b(-/-)) embryos rescues the early patterning defects in these mutants and the fish survive to adulthood. As injected RNA will only last, at most, for the first few days of embryogenesis, all later development occurs in the absence of bmp2b function. Although rescued swirl adult fish are viable, they have balance defects suggestive of vestibular dysfunction. Analysis of the inner ears of these fish reveals a total absence of semicircular canal ducts, structures involved in the detection of angular motion. All other regions of the ear, including the ampullae and cristae, are present and appear normal. Early stages of otic development in rescued swirl embryos are also normal. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate a critical late role for bmp2b in the morphogenesis of semicircular canals in the zebrafish inner ear. This is the first demonstration of a developmental role for any gene during post-embryonic stages of otic morphogenesis in the zebrafish. Despite differences in the early stages of semicircular canal formation between zebrafish and amniotes, the role of Bmp2 in semicircular canal duct outgrowth is likely to be conserved between different vertebrate species.

PMCID: PMC2629815 PMID: 19190757 [PubMed - indexed for MEDLINE]


34. J Neurosci. 2009 Jan 14;29(2):575-87.

Complementary actions of BDNF and neurotrophin-3 on the firing patterns and synaptic composition of motoneurons.

Davis-López de Carrizosa MA, Morado-Díaz CJ, Tena JJ, Benítez-Temiño B, Pecero ML, Morcuende SR, de la Cruz RR, Pastor AM.

Departamento de Fisiología y Zoología, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.

Neurotrophins, as target-derived factors, are essential for neuronal survival during development, but during adulthood, their scope of actions widens to become also mediators of synaptic and morphological plasticity. Target disconnection by axotomy produces an initial synaptic stripping ensued by synaptic rearrangement upon target reinnervation. Using abducens motoneurons of the oculomotor system as a model for axotomy, we report that trophic support by brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or a mixture of both, delivered to the stump of severed axons, results in either the prevention of synaptic stripping when administered immediately after lesion or in a promotion of reinnervation of afferents to abducens motoneurons once synaptic stripping had occurred, in concert with the recovery of synaptic potentials evoked from the vestibular nerve. Synaptotrophic effects, however, were larger when both neurotrophins were applied together. The axotomy-induced reduction in firing sensitivities related to eye movements were also restored to normal values when BDNF and NT-3 were administered, but discharge characteristics recovered in a complementary manner when only one neurotrophin was used. This is the first report to show selective retrograde trophic dependence of circuit-driven firing properties in vivo indicating that NT-3 restored the phasic firing, whereas BDNF supported the tonic firing of motoneurons during eye movement performance. Therefore, our data report a link between the synaptotrophic actions of neurotrophins, retrogradely delivered, and the alterations of neuronal firing patterns during motor behaviors. These trophic actions could be responsible, in part, for synaptic rearrangements that alter circuit stability and synaptic balance during plastic events of the brain.

PMID: 19144857 [PubMed - indexed for MEDLINE]


35. Dev Neurobiol. 2009 Feb 1-15;69(2-3):191-202.

Expression of the Pax2 transcription factor is associated with vestibular phenotype in the avian inner ear.

Warchol ME, Richardson GP.

Fay and Carl Simons Center for the Biology of Hearing and Deafness, Washington University School of Medicine, St. Louis, MO 63110, USA. warcholm@ent.wustl.edu

The paired-domain transcription factor Pax2 is involved in many facets of inner ear development, but relatively little is known about the expression or function of Pax2 in the mature ear. In this study, we have used immunohistochemical methods to characterize the expression patterns of Pax2 in the sensory organs of inner ears from posthatch chicks. Immunoreactivity for Pax2 was observed in the nuclei of most hair cells and supporting cells in the vestibular organs. In contrast, Pax2 expression in the chick cochlea was limited to hair cells located in the very distal (low frequency) region. We then used organotypic cultures of the chick utricle to examine changes in Pax2 expression in response to ototoxic injury and during hair cell regeneration. Treatment with streptomycin resulted in the loss of most Pax2 immunoreactivity from the lumenal (hair cell) stratum of the utricle. During the early phases of regeneration, moderate Pax2 expression was maintained in the nuclei of proliferating supporting cells. Expression of Pax2 in the hair cell stratum recovered in parallel with hair cell regeneration. The results indicate that Pax2 continues to be expressed in the mature avian ear, and that its expression pattern is correlated with a vestibular phenotype.

PMCID: PMC2731773 PMID: 19130600 [PubMed - indexed for MEDLINE]


36. Front Hum Neurosci. 2008;2:17. Epub 2008 Dec 3.

The vestibular component in out-of-body experiences: a computational approach.

Schwabe L, Blanke O.

Adaptive and Regenerative Software Systems, Department of Computer Science and Electrical Engineering Rostock, Germany. lars.schwabe@uni-rostock.de

Neurological evidence suggests that disturbed vestibular processing may play a key role in triggering out-of-body experiences (OBEs). Little is known about the brain mechanisms during such pathological conditions, despite recent experimental evidence that the scientific study of such experiences may facilitate the development of neurobiological models of a crucial aspect of self-consciousness: embodied self-location. Here we apply Bayesian modeling to vestibular processing and show that OBEs and the reported illusory changes of self-location and translation can be explained as the result of a mislead Bayesian inference, in the sense that ambiguous bottom-up signals from the vestibular otholiths in the supine body position are integrated with a top-down prior for the upright body position, which we measure during natural head movements. Our findings have relevance for self-location and translation under normal conditions and suggest novel ways to induce and study experimentally both aspects of bodily self-consciousness in healthy subjects.

PMCID: PMC2610253 PMID: 19115017 [PubMed]


37. AJNR Am J Neuroradiol. 2009 May;30(5):992-4. Epub 2008 Nov 27.

Communicating hydrocephalus after gamma knife radiosurgery for vestibular schwannoma: an MR imaging study.

Cauley KA, Ratkovits B, Braff SP, Linnell G.

Department of Radiology, University of Vermont College of Medicine, Burlington, VT, USA. keithcauley@hotmail.com

Vestibular schwannomas are common, and gamma knife radiosurgery is a treatment option of symptomatic tumors. Hydrocephalus may be a complication of gamma knife treatment of vestibular schwannoma, though the cause-and-effect relationship can be debated because tumors can cause hydrocephalus without treatment. We present an MR imaging study of an unusual case of communicating hydrocephalus after gamma knife radiosurgery of a vestibular schwannoma in which the timeline of events strongly suggests that gamma knife played a contributory role in the development of hydrocephalus. We discuss risk factors for the development of hydrocephalus after radiation therapy and the role of MR CSF cine-flow study in the evaluation of treatment options for hydrocephalus in this setting.

PMID: 19039040 [PubMed - indexed for MEDLINE]


38. Methods Mol Biol. 2009;493:311-21.

Identification of transcription factor-DNA interactions using chromatin immunoprecipitation assays.

Nie L, Vázquez AE, Yamoah EN.

Department of Otolaryngology, Center for Neuroscience, University of California, Davis CA, USA.

Expression of almost every gene is regulated at the transcription level. Therefore, transcriptional factor Transcription factors, consequently, have marked effects on the fate of a cell by establishing the gene expression patterns that determine biological processes. In the auditory and vestibular systems, transcription factors have been found to be responsible for development, cell growth, and apoptosis. It is vital to identify the transcription factor target genes and the mechanisms by which transcription factors control and guide gene expression and regulation pathways. Compared with earlier methods devised to study transcription factor-DNA interactions, the advantage of the chromatin immunoprecipitation (ChIP) assay is that the interaction of a transcription factor with its target genes is captured in the native context of chromatin in living cells. Therefore, ChIP base assays are powerful tools to identify the direct interaction of transcription factors and their target genes in vivo. More importantly, ChIP assays have been used in combination with molecular biology techniques, such as PCR and real time PCR, gene cloning, and DNA microarrays, to determine the interaction of transcription factor-DNA from a few potential individual targets to genome-wide surveys.

PMCID: PMC2822710 PMID: 18839356 [PubMed - indexed for MEDLINE]


39. Methods Mol Biol. 2009;493:141-62.

Isolation of sphere-forming stem cells from the mouse inner ear.

Oshima K, Senn P, Heller S.

Department of Otolaryngology-HNS, Stanford University School of Medicine, Stanford, CA, USA.

The mammalian inner ear has very limited ability to regenerate lost sensory hair cells. This deficiency becomes apparent when hair cell loss leads to hearing loss as a result of either ototoxic insult or the aging process. Coincidently, with this inability to regenerate lost hair cells, the adult cochlea does not appear to harbor cells with a proliferative capacity that could serve as progenitor cells for lost cells. In contrast, adult mammalian vestibular sensory epithelia display a limited ability for hair cell regeneration, and sphere-forming cells with stem cell features can be isolated from the adult murine vestibular system. The neonatal inner ear, however, does harbor sphere-forming stem cells residing in cochlear and vestibular tissues. Here, we provide protocols to isolate sphere-forming stem cells from neonatal vestibular and cochlear sensory epithelia as well as from the spiral ganglion. We further describe procedures for sphere propagation, cell differentiation, and characterization of inner ear cell types derived from spheres. Sphere-forming stem cells from the mouse inner ear are an important tool for the development of cellular replacement strategies of damaged inner ears and are a bona fide progenitor cell source for transplantation studies.

PMCID: PMC2861714 PMID: 18839346 [PubMed - indexed for MEDLINE]


40. J Vis. 2008 Aug 22;8(11):15.1-10.

Development of visually driven postural reactivity: a fully immersive virtual reality study.

Greffou S, Bertone A, Hanssens JM, Faubert J.

Visual Psychophysics and Perception Laboratory, School of Optometry, University of Montreal, Montreal, Quebec, Canada. selma.greffou@umontreal.ca

The objective of this study was to investigate the development of visually driven postural regulation in typically developing children of different ages. Thirty-two typically developing participants from 5 age groups (5-7 years, 8-11 years, 12-15 years, 16-19 years, or 20-25 years) were asked to stand within a virtual tunnel that oscillated in an anterior-posterior fashion at three different frequencies (0.125, 0.25, and 0.5 Hz). Body sway (BS) and postural perturbations (as measured by velocity root mean squared or vRMS) were measured. Most of the 5- to 7-year-old participants (67%) were unable to remain standing during the dynamic conditions. For older participants, BS decreased significantly with age for all frequencies. Moreover, vRMS decreased significantly from the 8- to 11- through 16- to 19-years age groups (greatest decreases for 0.5 Hz, followed by 0.25-Hz and 0.125-Hz conditions). No difference of frequency or instability was found between the 16- to 19- and 20- to 25-year-old groups for most conditions. Results suggest an over-reliance on visual input relative to proprioceptive and vestibular inputs on postural regulation at young ages (5-7 years). The finding that vRMS decreased significantly with age before stabilizing between 16 and 19 years suggests an important transitory period for sensorimotor development within this age range.

PMID: 18831609 [PubMed - indexed for MEDLINE]


41. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14609-14. Epub 2008 Sep 15.

A catechol-O-methyltransferase that is essential for auditory function in mice and humans.

Du X, Schwander M, Moresco EM, Viviani P, Haller C, Hildebrand MS, Pak K, Tarantino L, Roberts A, Richardson H, Koob G, Najmabadi H, Ryan AF, Smith RJ, Müller U, Beutler B.

Department of Genetics, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, CA 92037, USA.

We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of a chemically induced mutation responsible for a neurobehavioral phenotype. Mice homozygous for a missense mutation in Comt2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration of the organ of Corti. Consistent with this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear. COMT2 enzymatic activity is significantly reduced by the missense mutation, suggesting that a defect in catecholamine catabolism underlies the auditory and vestibular phenotypes. Based on the studies in mice, we have screened DNA from human families and identified a nonsense mutation in the human ortholog of the murine Comt2 gene that causes nonsyndromic deafness. Defects in catecholamine modification by COMT have been previously implicated in the development of schizophrenia. Our studies identify a previously undescribed COMT gene and indicate an unexpected role for catecholamines in the function of auditory and vestibular sense organs.

PMCID: PMC2567147 PMID: 18794526 [PubMed - indexed for MEDLINE]


42. J Neurophysiol. 2008 Oct;100(4):2287-99. Epub 2008 Aug 27.

Molecular identity and functional properties of a novel T-type Ca2+ channel cloned from the sensory epithelia of the mouse inner ear.

Nie L, Zhu J, Gratton MA, Liao A, Mu KJ, Nonner W, Richardson GP, Yamoah EN.

Center for Neuroscience, Program in Communication Science, University of California, Davis, 1544 Newton Ct., Davis, CA 95618, USA.

The molecular identity of non-Cav1.3 channels in auditory and vestibular hair cells has remained obscure, yet the evidence in support of their roles to promote diverse Ca2+-dependent functions is indisputable. Recently, a transient Cav3.1 current that serves as a functional signature for the development and regeneration of hair cells has been identified in the chicken basilar papilla. The Cav3.1 current promotes spontaneous activity of the developing hair cell, which may be essential for synapse formation. Here, we have isolated and sequenced the full-length complementary DNA of a distinct isoform of Cav3.1 in the mouse inner ear. The channel is derived from alternative splicing of exon14, exon25A, exon34, and exon35. Functional expression of the channel in Xenopus oocytes yielded Ca2+ currents, which have a permeation phenotype consistent with T-type channels. However, unlike most multiion channels, the T-type channel does not exhibit the anomalous mole fraction effect, possibly reflecting comparable permeation properties of divalent cations. The Cav3.1 channel was expressed in sensory and nonsensory epithelia of the inner ear. Moreover, there are profound changes in the expression levels during development. The differential expression of the channel during development and the pharmacology of the inner ear Cav3.1 channel may have contributed to the difficulties associated with identification of the non-Cav1.3 currents.

PMCID: PMC2576198 PMID: 18753322 [PubMed - indexed for MEDLINE]


43. J Neurosci. 2008 Aug 6;28(32):8086-95.

Semicircular canal size determines the developmental onset of angular vestibuloocular reflexes in larval Xenopus.

Lambert FM, Beck JC, Baker R, Straka H.

Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, Centre National de Recherche Scientifique, Unité Mixte de Recherche 7060, Université Paris Descartes, 75270 Paris Cedex 06, France.

Semicircular canals have been sensors of angular acceleration for 450 million years. This vertebrate adaptation enhances survival by implementing postural and visual stabilization during motion in a three-dimensional environment. We used an integrated neuroethological approach in larval Xenopus to demonstrate that semicircular canal dimensions, and not the function of other elements, determines the onset of angular acceleration detection. Before angular vestibuloocular function in either the vertical or horizontal planes, at stages 47 and 48, respectively, each individual component of the vestibuloocular system was shown to be operational: extraocular muscles could be activated, central neural pathways were complete, and canal hair cells were capable of evoking graded responses. For Xenopus, a minimum semicircular canal lumen radius of 60 microm was necessary to permit endolymph displacement sufficient for sensor function at peak accelerations of 400 degrees /s(2). An intra-animal comparison demonstrated that this size is reached in the vertical canals earlier in development than in the horizontal canals, corresponding to the earlier onset of vertical canal-activated ocular motor behavior. Because size constitutes a biophysical threshold for canal-evoked behavior in other vertebrates, such as zebrafish, we suggest that the semicircular canal lumen and canal circuit radius are limiting the onset of vestibular function in all small vertebrates. Given that the onset of gravitoinertial acceleration detection precedes angular acceleration detection by up to 10 d in Xenopus, these results question how the known precise spatial patterning of utricular and canal afferents in adults is achieved during development.

PMCID: PMC2647017 PMID: 18685033 [PubMed - indexed for MEDLINE]


44. Hum Mol Genet. 2008 Nov 1;17(21):3340-56. Epub 2008 Aug 4.

Eya1 gene dosage critically affects the development of sensory epithelia in the mammalian inner ear.

Zou D, Erickson C, Kim EH, Jin D, Fritzsch B, Xu PX.

McLaughlin Research Institute for Biomedical Sciences, Great Falls, MT 59405, USA.

Haploinsufficiency of the transcription co-activator EYA1 causes branchio-oto-renal syndrome, congenital birth defects that account for as many as 2% of profoundly deaf children; however, the underlying cause for its dosage requirement and its specific role in sensory cell development of the inner ear are unknown. Here, an allelic series of Eya1 were generated to study the basis of Eya1 dosage requirements for sensory organ development. Our results show different threshold requirements for the level of Eya1 in different regions of the inner ear. Short and disorganized hair cell sterocilia was observed in wild-type/null heterozygous or hypomorphic/hypomorphic homozygous cochleae. Patterning and gene-marker analyses indicate that in Eya1 hypomorphic/null heterozygous mice, a reduction of Eya1 expression to 21% of normal level causes an absence of cochlear and vestibular sensory formation. Eya1 is initially expressed in the progenitors throughout the epithelium of all six sensory regions, and later on during sensory cell differentiation, its expression becomes restricted to the differentiating hair cells. We provide genetic evidence that Eya1 activity, in a concentration-dependent manner, plays a key role in the regulation of genes known to be important for sensory development. Furthermore, we show that Eya1 co-localizes with Sox2 in the sensory progenitors and both proteins physically interact. Together, our results indicate that Eya1 appears to be upstream of very early events during the sensory organ development, hair cell differentiation and inner-ear patterning. These results also provide a molecular mechanism for understanding how hypomorphic levels of EYA1 cause inner-ear defects in humans.

PMCID: PMC2722896 PMID: 18678597 [PubMed - indexed for MEDLINE]


45. J Comp Neurol. 2008 Oct 1;510(4):378-95.

Comprehensive Wnt-related gene expression during cochlear duct development in chicken.

Sienknecht UJ, Fekete DM.

Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA.

The avian cochlear duct houses both a vestibular and auditory sensory organ (the lagena macula and basilar papilla, respectively), which each have a distinct structure and function. Comparative mRNA in situ hybridization mapping conducted over the time course of chicken cochlear duct development reveals that Wnt-related gene expression is concomitant with various developmental processes such as regionalization, convergent extension of the cochlear duct, cell fate specification, synaptogenesis, and the establishment of planar cell polarity. Wnts mostly originate from nonsensory tissue domains, whereas the sensory primordia preferentially transcribe Frizzled receptors, suggesting that paracrine Wnt signaling predominates in the cochlear duct. Superimposed over this is the strong expression of two secreted Frizzled-related Wnt inhibitors that tend to show complementary expression patterns. Frzb (SFRP3) is confined to the nonsensory cochlear duct and the lagena macula, whereas SFRP2 is maintained in the basilar papilla along with Fzd10 and Wnt7b. Flanking the basilar papilla are Wnt7a, Wnt9a, Wnt11, and SFRP2 on the neural side and Wnt5a, Wnt5b, and Wnt7a on the abneural side. The lateral nonsensory cochlear duct continuously expresses Frzb and temporarily expresses Wnt6 and SFRP1. Characteristic for the entire lagena is the expression of Frzb; in the lagena macula are Fzd1, Fzd7, and Wnt7b, and in the nonsensory tissues are Wnt4 and Wnt5a. Auditory hair cells preferentially express Fzd2 and Fzd9, whereas the main receptors expressed in vestibular hair cells are Fzd1 and Fzd7, in addition to Fzd2 and Fzd9.

PMCID: PMC2566905 PMID: 18671253 [PubMed - indexed for MEDLINE]


46. Braz J Otorhinolaryngol. 2008 May-Jun;74(3):342-9.

Audiological study of an elderly Brazilian population.

do Carmo LC, Médicis da Silveira JA, Marone SA, D'Ottaviano FG, Zagati LL, Dias von Söhsten Lins EM.

University of São Paulo Medical School, Brazil.

The Brazilian elderly population is growing, and already represents 8,6% of our total population. Environmental factors, lifestyle, gender and genetics impact the development of presbycusis, which reduces quality of life. AIM: investigate audiologic and vestibular complaints in the elderly; perform tonal audiometry and check to see if there are differences between genders. STUDY: Cross-sectional clinical prospective study. MATERIALS AND METHODS: 320 elderly patients (160 men and 160 women) were submitted to audiologic interview and tonal audiometry. The results were statistically analyzed by the following methods: ANOVA, Mann-Whitney and Chi-Squared. RESULTS: audiologic and vestibular complaints (hearing loss, tinnitus, ear fullness, dizziness) were similar between the genders (except for dizziness: p<0,05); tonal audiometry showed a significant difference, with hearing loss in the high frequencies among men; and among women the curves were descending and flat. These results were statistically significant (P<0,001). CONCLUSION: our results lead us to conclude that, when the genders are compared, hearing loss in the elderly has similar symptoms; however, there are significant differences in tonal audiometry.

PMID: 18661006 [PubMed - indexed for MEDLINE]


47. J Neurosci. 2008 Jun 25;28(26):6633-41.

Jxc1/Sobp, encoding a nuclear zinc finger protein, is critical for cochlear growth, cell fate, and patterning of the organ of corti.

Chen Z, Montcouquiol M, Calderon R, Jenkins NA, Copeland NG, Kelley MW, Noben-Trauth K.

Sections on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.

The mouse cochlea emerges from the ventral pole of the otocyst to form a one and three-quarter coil. Little is known about the factors that control the growth of the cochlea. Jackson circler (jc) is a recessive mutation causing deafness resulting from a growth arrest of the cochlea duct at day 13.5 of embryonic development. Here, we identify the vertebrate homolog of the Drosophila Sobp (sine oculis-binding protein) gene (named Jxc1) in the jc locus. Jxc1 encodes a nuclear protein that has two FCS-type zinc finger domains (PS51024) and bears nuclear localization signals and highly conserved sequence motifs. Transiently expressed wild-type protein is targeted to the nucleus, but mutant isoforms were mislocalized in the cytoplasm. In jc mutants, the cellular patterning of the organ of Corti is severely disrupted, exhibiting supernumerary hair cells at the apex, showing mirror-image duplications of tunnel of Corti and inner hair cells, and expressing ectopic vestibular-like hair cells within Kölliker's organ. Jxc1 mRNA was detected in inner ear sensory hair cells, supporting cells, and the acoustic ganglia. Expression was also found in the developing retina, olfactory epithelium, trigeminal ganglion, and hair follicles. Collectively, our data support a role for Jxc1 in controlling a critical step in cochlear growth, cell fate, and patterning of the organ of Corti.

PMCID: PMC2556235 PMID: 18579736 [PubMed - indexed for MEDLINE]


48. J Comp Neurol. 2008 Aug 20;509(6):661-76.

Espin actin-cytoskeletal proteins are in rat type I spiral ganglion neurons and include splice-isoforms with a functional nuclear localization signal.

Sekerková G, Zheng L, Mugnaini E, Bartles JR.

Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. g-sekerkova@northwestern.edu

The espins are Ca(2+)-resistant actin-bundling proteins that are enriched in hair cell stereocilia and sensory cell microvilli. Here, we report a novel localization of espins to a large proportion of rat type I spiral ganglion neurons (SGNs) and their projections to the cochlear nucleus (CN). Moreover, we show that a fraction of these espins is in the nucleus of SGNs owing to the presence of splice-isoforms that contain a functional nuclear localization signal (NLS). Espin antibody labeled approximately 83% of type I SGNs, and the labeling intensity increased dramatically during early postnatal development. Type II SGNs and vestibular ganglion neurons were unlabeled. In the CN, espin-positive auditory nerve fibers showed a projection pattern typical of type I SGNs, with intense labeling in the nerve root region and posteroventral CN (PVCN). The anteroventral CN (AVCN) showed moderate labeling, whereas the dorsal CN showed weak labeling that was restricted to the deep layer. Espin-positive synaptic terminals were enriched around nerve root neurons and octopus cells in the PVCN and were also found on globular bushy cells and multipolar neurons in the PVCN and AVCN. SGNs expressed multiple espin transcripts and proteins, including splice-isoforms that contain a nonapeptide, which is rich in positively charged amino acids and creates a bipartite NLS. The nonapeptide was necessary to target espin isoforms to the nucleus and was sufficient to target an unrelated protein to the nucleus when joined with the upstream di-arginine-containing octapeptide. The presence of cytoplasmic and nuclear espins in SGNs suggests additional roles for espins in auditory neuroscience. Copyright 2008 Wiley-Liss, Inc.

PMCID: PMC2574652 PMID: 18551532 [PubMed - indexed for MEDLINE]


49. PLoS Genet. 2008 Apr 11;4(4):e1000050.

Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements.

Chang W, Lin Z, Kulessa H, Hebert J, Hogan BL, Wu DK.

National Institute on Deafness and Other Communication Disorders, NIH, Rockville, Maryland, United States of America.

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.

PMCID: PMC2274953 PMID: 18404215 [PubMed - indexed for MEDLINE]


50. Braz J Otorhinolaryngol. 2008 Jan-Feb;74(1):125-31.

Mobile phones: influence on auditory and vestibular systems.

Balbani AP, Montovani JC.

Faculdade de Medicina de Botucatu, UNESP, SP, Brazil. a_balbani@hotmail.com

Erratum in:

   Rev Bras Otorrinolaringol (Engl Ed). 2008 Mar-Apr;74(2):319.

Telecommunications systems emit radiofrequency, which is an invisible electromagnetic radiation. Mobile phones operate with microwaves (450900 MHz in the analog service, and 1,82,2 GHz in the digital service) very close to the users ear. The skin, inner ear, cochlear nerve and the temporal lobe surface absorb the radiofrequency energy. AIM: literature review on the influence of cellular phones on hearing and balance. STUDY DESIGN: systematic review. METHODS: We reviewed papers on the influence of mobile phones on auditory and vestibular systems from Lilacs and Medline databases, published from 2000 to 2005, and also materials available in the Internet. RESULTS: Studies concerning mobile phone radiation and risk of developing an acoustic neuroma have controversial results. Some authors did not see evidences of a higher risk of tumor development in mobile phone users, while others report that usage of analog cellular phones for ten or more years increase the risk of developing the tumor. Acute exposure to mobile phone microwaves do not influence the cochlear outer hair cells function in vivo and in vitro, the cochlear nerve electrical properties nor the vestibular system physiology in humans. Analog hearing aids are more susceptible to the electromagnetic interference caused by digital mobile phones. CONCLUSION: there is no evidence of cochleo-vestibular lesion caused by cellular phones.

PMID: 18392513 [PubMed - indexed for MEDLINE]


51. J Neurosurg. 2008 Apr;108(4):751-6.

The vestibular aqueduct: site of origin of endolymphatic sac tumors.

Lonser RR, Baggenstos M, Kim HJ, Butman JA, Vortmeyer AO.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA. lonserr@ninds.nih.gov

Comment in:

   J Neurosurg. 2008 Sep;109(3):569-70; author reply 570.

OBJECT: Although endolymphatic sac tumors (ELSTs) frequently destroy the posterior petrous bone and cause hearing loss, the anatomical origin of these neoplasms is unknown. To determine the precise topographic origin of ELSTs, the authors analyzed the imaging, operative, and pathological findings in patients with von Hippel-Lindau disease (VHL) and ELSTs. METHODS: Consecutive VHL patients with small (<or= 1.5 cm) ELSTs who underwent resection at the National Institutes of Health were included. Clinical, imaging, operative, and pathological findings were analyzed. RESULTS: Ten consecutive VHL patients (6 male and 4 female) with 10 small ELSTs (<or= 1.5 cm; 9 left, 1 right) were included. Serial imaging captured the development of 6 ELSTs and revealed that they originated within the intraosseous (vestibular aqueduct) portion of the endolymphatic duct/sac system. Imaging just before surgery demonstrated that the epicenters of 9 ELSTs (1 ELST was not visible on preoperative imaging) were in the vestibular aqueduct. Inspection during surgery established that all 10 ELSTs were limited to the intraosseous endolymphatic duct/sac and the immediately surrounding region. Histological analysis confirmed tumor within the intraosseous portion (vestibular aqueduct) of the endolymphatic duct/sac in all 10 patients. CONCLUSIONS: ELSTs originate from endolymphatic epithelium within the vestibular aqueduct. High-resolution imaging through the region of the vestibular aqueduct is essential for diagnosis. Surgical exploration of the endolymphatic duct and sac is required for complete resection.

PMCID: PMC2770700 PMID: 18377255 [PubMed - indexed for MEDLINE]


52. Acta Otorrinolaringol Esp. 2008 Feb;59(2):76-9.

[Peripheral vertigo classification. Consensus document. Otoneurology committee of the Spanish otorhinolaryngology society (2003-2006)]

[Article in Spanish]

Morera C, Pérez H, Pérez N, Soto A; Comisión de Otoneurología de la Sociedad Española de Otorrinolaringología.

Hospital Universitario la Fe, Universidad de Valencia, Valencia, España.

There are many different vertigo classifications and different denominations are frequently used for the same clinical processes. The Otoneurology Committee of the Spanish Society for Otorhinolaryngology and Head and Neck Pathology proposes an eminently practical classification of peripheral vertigo to facilitate a common terminology that can be easily used by the general ENT practitioners. The methodology used has been by consensus within our Society and especially among the most outstanding work groups in the area of otoneurology in Spain. Initially vertigo is divided into single-episode vertigo and recurring attacks of vertigo, and these are then sub-divided into 2 groups, depending on whether or not hearing loss is present. Acute vertigo without hearing loss corresponds to vestibular neuritis and if it is associated with hearing loss, it is due to labyrinthitis of different aetiologies and cochleo-vestibular neuritis. Recurrent vertigos without hearing loss are classified as induced, either by posture (BPPV) or pressure (perilymphatic fistula), or as spontaneous, including migraine-associated vertigo, metabolic vertigo, childhood paroxysmal vertigo and vertigo of vascular causes (AITs, vertebral-basilar failure). Finally, recurrent vertigo with hearing loss includes Ménière's disease and others such as vertigo-migraine (with hearing loss), autoimmune pathology of the inner ear, syphilitic infection, and perilymphatic fistula (with hearing loss).

PMID: 18341864 [PubMed - indexed for MEDLINE]


53. Development. 2008 Apr;135(8):1427-37. Epub 2008 Mar 13.

A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth.

Lefèvre G, Michel V, Weil D, Lepelletier L, Bizard E, Wolfrum U, Hardelin JP, Petit C.

Unité de Génétique des Déficits Sensoriels, UMRS587 INSERM-Université Paris VI, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France.

The planar polarity and staircase-like pattern of the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15 or sans cause Usher syndrome type I (USH1, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans and hair bundle disorganization in mice. Whether the USH1 proteins are involved in common hair bundle morphogenetic processes is unknown. Here, we show that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-52 degrees mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17. Abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin 23 and protocadherin 15, all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth, harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin 23 and protocadherin 15. This positional change did not occur in mice deficient for cadherin 23 or protocadherin 15. We suggest that tension forces applied to the early lateral links and to the tip link, both of which can be anchored to actin filaments via harmonin-b, play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter.

PMID: 18339676 [PubMed - indexed for MEDLINE]


54. Dev Dyn. 2008 Apr;237(4):941-52.

The transmembrane inner ear (tmie) gene contributes to vestibular and lateral line development and function in the zebrafish (Danio rerio).

Shen YC, Jeyabalan AK, Wu KL, Hunker KL, Kohrman DC, Thompson DL, Liu D, Barald KF.

Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.

The inner ear is a complex organ containing sensory tissue, including hair cells, the development of which is not well understood. Our long-term goal is to discover genes critical for the correct formation and function of the inner ear and its sensory tissue. A novel gene, transmembrane inner ear (Tmie), was found to cause hearing-related disorders when defective in mice and humans. A homologous tmie gene in zebrafish was cloned and its expression characterized between 24 and 51 hours post-fertilization. Embryos injected with morpholinos (MO) directed against tmie exhibited circling swimming behavior (approximately 37%), phenocopying mice with Tmie mutations; semicircular canal formation was disrupted, hair cell numbers were reduced, and maturation of electrically active lateral line neuromasts was delayed. As in the mouse, tmie appears to be required for inner ear development and function in the zebrafish and for hair cell maturation in the vestibular and lateral line systems as well. (c) 2008 Wiley-Liss, Inc.

PMID: 18330929 [PubMed - indexed for MEDLINE]


55. Behav Neurosci. 2008 Feb;122(1):224-32.

Orbital spaceflight during pregnancy shapes function of mammalian vestibular system.

Ronca AE, Fritzsch B, Bruce LL, Alberts JR.

Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. aronca@wfubmc.edu

Pregnant rats were flown on the NASA Space Shuttle during the early developmental period of their fetuses' vestibular apparatus and onset of vestibular function. The authors report that prenatal spaceflight exposure shapes vestibular-mediated behavior and central morphology. Postflight testing revealed (a) delayed onset of body righting responses, (b) cardiac deceleration (bradycardia) to 70 degrees head-up roll, (c) decreased branching of gravistatic afferent axons, but (d) no change in branching of angular acceleration receptor projections with comparable synaptogenesis of the medial vestibular nucleus in flight relative to control fetuses. Kinematic analyses of the dams' on-orbit behavior suggest that, although the fetal otolith organs are unloaded in microgravity, the fetus' semicircular canals receive high levels of stimulation during longitudinal rotations of the mother's weightless body. Behaviorally derived stimulation from maternal movements may be a significant factor in studies of vestibular sensory development. Taken together, these studies provide evidence that gravity and angular acceleration shape prenatal organization and function within the mammalian vestibular system. Copyright (c) 2008 APA, all rights reserved.

PMCID: PMC2610337 PMID: 18298265 [PubMed - indexed for MEDLINE]


56. J Clin Invest. 2008 Mar;118(3):1176-85.

Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice.

Nakano Y, Longo-Guess CM, Bergstrom DE, Nauseef WM, Jones SM, Bánfi B.

Department of Anatomy and Cell Biology, Inflammation Program, University of Iowa, Iowa City, Iowa, USA.

In humans, hereditary inactivation of either p22(phox) or gp91(phox) leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22(phox) and gp91(phox) proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22(phox) deficiency. Characterization of nmf333 mice revealed that deletion of p22(phox) inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22(phox)-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22(phox) represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22(phox) expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.

PMCID: PMC2248803 PMID: 18292807 [PubMed - indexed for MEDLINE]


57. IEEE Rev Biomed Eng. 2008 Jan 1;1:115-142.

Cochlear Implants:System Design, Integration and Evaluation.

Zeng FG, Rebscher S, Harrison WV, Sun X, Feng H.

Departments of Anatomy and Neurobiology, Biomedical Engineering, Cognitive Sciences and Otolaryngology - Head and Neck Surgery, University of California, 364 Med Surg II, Irvine, CA 92697, USA ( fzeng@uci.edu ).

As the most successful neural prosthesis, cochlear implants have provided partial hearing to more than 120,000 persons worldwide; half of which being pediatric users who are able to develop nearly normal language. Biomedical engineers have played a central role in the design, integration and evaluation of the cochlear implant system, but the overall success is a result of collaborative work with physiologists, psychologists, physicians, educators, and entrepreneurs. This review presents broad yet in-depth academic and industrial perspectives on the underlying research and ongoing development of cochlear implants. The introduction accounts for major events and advances in cochlear implants, including dynamic interplays among engineers, scientists, physicians, and policy makers. The review takes a system approach to address critical issues from design and specifications to integration and evaluation. First, the cochlear implant system design and specifications are laid out. Second, the design goals, principles, and methods of the subsystem components are identified from the external speech processor and radio frequency transmission link to the internal receiver, stimulator and electrode arrays. Third, system integration and functional evaluation are presented with respect to safety, reliability, and challenges facing the present and future cochlear implant designers and users. Finally, issues beyond cochlear implants are discussed to address treatment options for the entire spectrum of hearing impairment as well as to use the cochlear implant as a model to design and evaluate other similar neural prostheses such as vestibular and retinal implants.

PMCID: PMC2782849 PMID: 19946565 [PubMed]


58. J Assoc Res Otolaryngol. 2008 Mar;9(1):65-89. Epub 2007 Dec 22.

Sox2 and JAGGED1 expression in normal and drug-damaged adult mouse inner ear.

Oesterle EC, Campbell S, Taylor RR, Forge A, Hume CR.

Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington, CHDD CD176, Box 357923, Seattle, WA 98195-7923, USA. oesterle@u.washington.edu

Inner ear hair cells detect environmental signals associated with hearing, balance, and body orientation. In humans and other mammals, significant hair cell loss leads to irreversible hearing and balance deficits, whereas hair cell loss in nonmammalian vertebrates is repaired by the spontaneous generation of replacement hair cells. Research in mammalian hair cell regeneration is hampered by the lack of in vivo damage models for the adult mouse inner ear and the paucity of cell-type-specific markers for non-sensory cells within the sensory receptor epithelia. The present study delineates a protocol to drug damage the adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol to investigate Sox2 and Jagged1 expression in damaged inner ear sensory epithelia. In other tissues, the transcription factor Sox2 and a ligand member of the Notch signaling pathway, Jagged1, are involved in regenerative processes. Both are involved in early inner ear development and are expressed in developing support cells, but little is known about their expressions in the adult. We describe a nonsurgical technique for inducing hair cell damage in adult mouse organ of Corti by a single high-dose injection of the aminoglycoside kanamycin followed by a single injection of the loop diuretic furosemide. This drug combination causes the rapid death of outer hair cells throughout the cochlea. Using immunocytochemical techniques, Sox2 is shown to be expressed specifically in support cells in normal adult mouse inner ear and is not affected by drug damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of vestibular hair cells. Double-labeling experiments with Sox2 and calbindin suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in support cells in the adult ear and is not affected by drug damage. Sox2 and Jagged1 may be involved in the maintenance of support cells in adult mouse inner ear.

PMCID: PMC2536811 PMID: 18157569 [PubMed - indexed for MEDLINE]


59. J Neurosci. 2007 Dec 19;27(51):14078-88.

Auditory neurons make stereotyped wiring decisions before maturation of their targets.

Koundakjian EJ, Appler JL, Goodrich LV.

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Cochlear ganglion neurons communicate sound information from cochlear hair cells to auditory brainstem neurons through precisely wired circuits. Understanding auditory circuit assembly is a significant challenge because of the small size of the otic vesicle and difficulties labeling and imaging embryonic neurons. We used genetic fate mapping in the mouse to visualize the morphologies of individual cochlear ganglion neurons throughout development, from their origin in the Neurogenin1-positive neurogenic domain in the otic vesicle to the formation of connections with targets in the cochlea and in the cochlear nucleus. We found that auditory neurons with different patterns of connectivity arise from discrete populations of Neurogenin1-positive precursors that make stereotyped wiring decisions depending on when and where they are born. Auditory precursors are segregated from vestibular precursors early in neurogenesis. Within this population, cochlear ganglion neurons with type I and type II morphologies are apparent before birth and develop within common pools of precursors. The peripheral projections are initially complex and branched and then become simple and straight after reaching the edge of the sensory epithelium. Subsequently, a small number of projections attain obvious type II morphologies, beginning at embryonic day 16.5 (E16.5), when hair cells begin to differentiate. Centrally, cochlear ganglion axons are topographically organized in the auditory brainstem as early as E15.5, when the cochlear nucleus is still immature. These findings suggest that Neurogenin1 precursors possess intrinsic programs of differentiation that direct early auditory circuit assembly events before the maturation of presynaptic and postsynaptic target cells.

PMID: 18094247 [PubMed - indexed for MEDLINE]


60. Development. 2007 Dec;134(24):4405-15.

Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development.

Raft S, Koundakjian EJ, Quinones H, Jayasena CS, Goodrich LV, Johnson JE, Segil N, Groves AK.

Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 West 3rd Street, Los Angeles CA 90057, USA.

Temporal and spatial coordination of multiple cell fate decisions is essential for proper organogenesis. Here, we define gene interactions that transform the neurogenic epithelium of the developing inner ear into specialized mechanosensory receptors. By Cre-loxP fate mapping, we show that vestibular sensory hair cells derive from a previously neurogenic region of the inner ear. The related bHLH genes Ngn1 (Neurog1) and Math1 (Atoh1) are required, respectively, for neural and sensory epithelial development in this system. Our analysis of mouse mutants indicates that a mutual antagonism between Ngn1 and Math1 regulates the transition from neurogenesis to sensory cell production during ear development. Furthermore, we provide evidence that the transition to sensory cell production involves distinct autoregulatory behaviors of Ngn1 (negative) and Math1 (positive). We propose that Ngn1, as well as promoting neurogenesis, maintains an uncommitted progenitor cell population through Notch-mediated lateral inhibition, and Math1 irreversibly commits these progenitors to a hair-cell fate.

PMID: 18039969 [PubMed - indexed for MEDLINE]


61. Int J Dev Biol. 2007;51(6-7):585-95.

Pocket proteins and cell cycle regulation in inner ear development.

Rocha-Sanchez SM, Beisel KW.

Creighton University School of Dentistry, Dept of Oral Biology, Omaha, NE 68178, USA. ssanchez@creighton.edu

Loss of neurosensory cells of the ear, caused by genetic and non-genetic factors, is becoming an increasing problem as people age, resulting in deafness and vestibular disorders. Unveiling useful mechanisms of cell cycle regulation may offer the possibility to generate new cells out of remaining ones, thus providing the cellular basis to induce new hair cell differentiation in the mammalian ear. Here, we provide an overview of cell cycle regulating genes in general and of those studied in the ear in particular. We categorize those genes into regulators that act upstream of the pocket proteins and into those that act downstream of the pocket proteins. The three members of the pocket protein family essentially determine, through interaction with the eight members of the E2F family, whether or not the cell cycle will progress to the S-phase and thus cell division. The abundant presence of one or more members of these families in adult hair cells supports the notion that inhibition of cell cycle progression through these proteins is a lifelong process. Indeed, manipulating some of those proteins, unfortunately, leads to abortive entry into the cell cycle. Combined with recent success to induce hair cell differentiation through molecular therapy, these approaches may provide a viable strategy to restore lost hair cells in the inner ear.

PMID: 17891719 [PubMed - indexed for MEDLINE]


62. Mamm Genome. 2007 Sep;18(9):646-56. Epub 2007 Sep 18.

Targeted knockout and lacZ reporter expression of the mouse Tmhs deafness gene and characterization of the hscy-2J mutation.

Longo-Guess CM, Gagnon LH, Fritzsch B, Johnson KR.

The Jackson Laboratory, Bar Harbor, ME 04609, USA.

The Tmhs gene codes for a tetraspan transmembrane protein that is expressed in hair cell stereocilia. We previously showed that a spontaneous missense mutation of Tmhs underlies deafness and vestibular dysfunction in the hurry-scurry (hscy) mouse. Subsequently, mutations in the human TMHS gene were shown to be responsible for DFNB67, an autosomal recessive nonsyndromic deafness locus. Here we describe a genetically engineered null mutation of the mouse Tmhs gene (Tmhs ( tm1Kjn )) and show that its phenotype is identical to that of the hscy missense mutation, confirming the deleterious nature of the hscy cysteine-to-phenylalanine substitution. In the targeted null allele, the Tmhs promoter drives expression of a lacZ reporter gene. Visualization of beta-galactosidase activity in Tmhs ( tm1Kjn ) heterozygous mice indicates that Tmhs is highly expressed in the cochlear and vestibular hair cells of the inner ear. Expression is first detectable at E15.5, peaks around P0, decreases slightly at P6, and is absent by P15, a duration that supports the involvement of Tmhs in stereocilia development. Tmhs reporter gene expression also was detected in several cranial and cervical sensory ganglia, but not in the vestibular or spiral ganglia. We also describe a new nontargeted mutation of the Tmhs gene, hscy-2J, that causes abnormal splicing from a cryptic splice site within exon 2 and is predicted to produce a functionally null protein lacking 51 amino acids of the wild-type sequence.

PMCID: PMC2613174 PMID: 17876667 [PubMed - indexed for MEDLINE]


63. Development. 2007 Oct;134(20):3615-25. Epub 2007 Sep 12.

Fgf3 is required for dorsal patterning and morphogenesis of the inner ear epithelium.

Hatch EP, Noyes CA, Wang X, Wright TJ, Mansour SL.

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112-5330, USA.

The inner ear, which contains sensory organs specialized for hearing and balance, develops from an ectodermal placode that invaginates lateral to hindbrain rhombomeres (r) 5-6 to form the otic vesicle. Under the influence of signals from intra- and extraotic sources, the vesicle is molecularly patterned and undergoes morphogenesis and cell-type differentiation to acquire its distinct functional compartments. We show in mouse that Fgf3, which is expressed in the hindbrain from otic induction through endolymphatic duct outgrowth, and in the prospective neurosensory domain of the otic epithelium as morphogenesis initiates, is required for both auditory and vestibular function. We provide new morphologic data on otic dysmorphogenesis in Fgf3 mutants, which show a range of malformations similar to those of Mafb (Kreisler), Hoxa1 and Gbx2 mutants, the most common phenotype being failure of endolymphatic duct and common crus formation, accompanied by epithelial dilatation and reduced cochlear coiling. The malformations have close parallels with those seen in hearing-impaired patients. The morphologic data, together with an analysis of changes in the molecular patterning of Fgf3 mutant otic vesicles, and comparisons with other mutations affecting otic morphogenesis, allow placement of Fgf3 between hindbrain-expressed Hoxa1 and Mafb, and otic vesicle-expressed Gbx2, in the genetic cascade initiated by WNT signaling that leads to dorsal otic patterning and endolymphatic duct formation. Finally, we show that Fgf3 prevents ventral expansion of r5-6 neurectodermal Wnt3a, serving to focus inductive WNT signals on the dorsal otic vesicle and highlighting a new example of cross-talk between the two signaling systems.

PMCID: PMC2366212 PMID: 17855431 [PubMed - indexed for MEDLINE]


64. Dev Biol. 2007 Oct 15;310(2):329-40. Epub 2007 Aug 9.

In vivo genetic ablation of the periotic mesoderm affects cell proliferation survival and differentiation in the cochlea.

Xu H, Chen L, Baldini A.

Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.

Tbx1 is required for ear development in humans and mice. Gene manipulation in the mouse has discovered multiple consequences of loss of function on early development of the inner ear, some of which are attributable to a cell autonomous role in maintaining cell proliferation of epithelial progenitors of the cochlear and vestibular apparata. However, ablation of the mesodermal domain of the gene also results in severe but more restricted abnormalities. Here we show that Tbx1 has a dynamic expression during late development of the ear, in particular, is expressed in the sensory epithelium of the vestibular organs but not of the cochlea. Vice versa, it is expressed in the condensed mesenchyme that surrounds the cochlea but not in the one that surrounds the vestibule. Loss of Tbx1 in the mesoderm disrupts this peri-cochlear capsule by strongly reducing the proliferation of mesenchymal cells. The organogenesis of the cochlea, which normally occurs inside the capsule, was dramatically affected in terms of growth of the organ, as well as proliferation, differentiation and survival of its epithelial cells. This model provides a striking demonstration of the essential role played by the periotic mesenchyme in the organogenesis of the cochlea.

PMCID: PMC2223065 PMID: 17825816 [PubMed - indexed for MEDLINE]


65. Psychosom Med. 2007 Sep-Oct;69(7):700-7. Epub 2007 Aug 31.

Predicting continued dizziness after an acute peripheral vestibular disorder.

Heinrichs N, Edler C, Eskens S, Mielczarek MM, Moschner C.

Institute of Psychology, Technical University of Braunschweig, Spielmannstr. 12a, 38106 Braunschweig, Germany. n.heinrichs@tu-bs.de

OBJECTIVE: To identify individuals at risk of developing ongoing dizziness 3 months after an acute peripheral vestibular disorder episode, which is usually functionally compensated or even healed within a few weeks. METHODS: In a prospective longitudinal study, we assessed fear of bodily sensations and cognitions related to anxiety at the time of hospital admission and 3 months later in 43 patients with an episode of vestibular neuritis (VN) or benign paroxysmal positional vertigo (BPPV). All participants were assessed for mental disorders using a structured clinical interview. RESULTS: Only the interaction between fear of bodily sensations within the first 2 weeks after admission and the type of vestibular disorder predicted the extent of dizzy complaints 3 months later; this accounts for 21% of the variance in a multiple regression analysis. Specifically, the prediction was valid only in patients with VN but not in patients with BPPV. Further analysis demonstrated that the interaction was not due to the peripheral vestibular disorder per se but rather determined by the initial severity of dizziness, which was significantly different in BPPV and VN patients. CONCLUSIONS: The present study demonstrates that, for the development of persistent psychogenic dizziness after a peripheral vestibular disorder, the fear of bodily sensations is only relevant in interaction with the initial severity of dizziness experienced during the acute organic episode. To prevent development of persistent psychogenic dizziness, we feel that our results indicate the need to screen patients with vestibular disorders for at-risk status and offer them psychological support to deal with their symptoms.

PMID: 17766688 [PubMed - indexed for MEDLINE]


66. J Neurosci. 2007 Aug 15;27(33):8940-51.

Dominant-negative inhibition of M-like potassium conductances in hair cells of the mouse inner ear.

Holt JR, Stauffer EA, Abraham D, Géléoc GS.

Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA. jeffholt@virginia.edu

Sensory hair cells of the inner ear express multiple physiologically defined conductances, including mechanotransduction, Ca(2+), Na(+), and several distinct K(+) conductances, all of which are critical for normal hearing and balance function. Yet, the molecular underpinnings and their specific contributions to sensory signaling in the inner ear remain obscure. We sought to identify hair-cell conductances mediated by KCNQ4, which, when mutated, causes the dominant progressive hearing loss DFNA2. We used the dominant-negative pore mutation G285S and packaged the coding sequence of KCNQ4 into adenoviral vectors. We transfected auditory and vestibular hair cells of organotypic cultures generated from the postnatal mouse inner ear. Cochlear outer hair cells and vestibular type I cells that expressed the transfection marker, green fluorescent protein, and the dominant-negative KCNQ4 construct lacked the M-like conductances that typify nontransfected control hair cells. As such, we conclude that the M-like conductances in mouse auditory and vestibular hair cells can include KCNQ4 subunits and may also include KCNQ4 coassembly partners. To examine the function of M-like conductances in hair cells, we recorded from cells transfected with mutant KCNQ4 and injected transduction current waveforms in current-clamp mode. Because the M-like conductances were active at rest, they contributed to the very low potassium-selective input resistance, which in turn hyperpolarized the resting potential and significantly attenuated the amplitude of the receptor potential. Modulation of M-like conductances may allow hair cells the ability to control the amplitude of their response to sensory stimuli.

PMCID: PMC2647843 PMID: 17699675 [PubMed - indexed for MEDLINE]


67. J Physiol. 2007 Sep 15;583(Pt 3):923-43. Epub 2007 Jul 12.

Developmental regulation of the membrane properties of central vestibular neurons by sensory vestibular information in the mouse.

Eugène D, Deforges S, Guimont F, Idoux E, Vidal PP, Moore LE, Vibert N.

Laboratoire de Neurobiologie des Réseaux Sensorimoteurs, UMR 7060, CNRS-Université Paris Descartes, Paris. daniel.eugene@univ-paris5.fr

Comment in:

   J Physiol. 2007 Sep 15;583(Pt 3):815.

The effect of the lack of vestibular input on the membrane properties of central vestibular neurons was studied by using a strain of transgenic, vestibular-deficient mutant KCNE1(-/-) mice where the hair cells of the inner ear degenerate just after birth. Despite the absence of sensory vestibular input, their central vestibular pathways are intact. Juvenile and adult homozygous mutant have a normal resting posture, but show a constant head bobbing behaviour and display the shaker/waltzer phenotype characterized by rapid bilateral circling during locomotion. In juvenile mice, the KCNE1 mutation was associated with a strong decrease in the expression of the calcium-binding proteins calbindin, calretinin and parvalbumin within the medial vestibular nucleus (MVN) and important modifications of the membrane properties of MVN neurons. In adult mice, however, there was almost no difference between the membrane properties of MVN neurons of homozygous and control or heterozygous mutant mice, which have normal inner ear hair cells and show no behavioural symptoms. The expression levels of calbindin and calretinin were lower in adult homozygous mutant animals, but the amount of calcium-binding proteins expressed in the MVN was much greater than in juvenile mice. These data demonstrate that suppression of sensory vestibular inputs during a 'sensitive period' around birth can generate the circling/waltzing behaviour, but that this behaviour is not due to persistent abnormalities of the membrane properties of central vestibular neurons. Altogether, maturation of the membrane properties of central vestibular neurons is delayed, but not impaired by the absence of sensory vestibular information.

PMCID: PMC2277192 PMID: 17627998 [PubMed - indexed for MEDLINE]


68. J Neurophysiol. 2007 Sep;98(3):1549-65. Epub 2007 Jul 11.

Activity of vestibular nuclei neurons during vestibular and optokinetic stimulation in the alert mouse.

Beraneck M, Cullen KE.

Department of Physiology, McGill University, Montreal, Quebec, Canada. Mathieu.beraneck@univ-paris5.fr

As a result of the availability of genetic mutant strains and development of noninvasive eye movements recording techniques, the mouse stands as a very interesting model for bridging the gap among behavioral responses, neuronal response dynamics studied in vivo, and cellular mechanisms investigated in vitro. Here we characterized the responses of individual neurons in the mouse vestibular nuclei during vestibular (horizontal whole body rotations) and full field visual stimulation. The majority of neurons ( approximately 2/3) were sensitive to vestibular stimulation but not to eye movements. During the vestibular-ocular reflex (VOR), these neurons discharged in a manner comparable to the "vestibular only" (VO) neurons that have been previously described in primates. The remaining neurons [eye-movement-sensitive (ES) neurons] encoded both head-velocity and eye-position information during the VOR. When vestibular and visual stimulation were applied so that there was sensory conflict, the behavioral gain of the VOR was reduced. In turn, the modulation of sensitivity of VO neurons remained unaffected, whereas that of ES neurons was reduced. ES neurons were also modulated in response to full field visual stimulation that evoked the optokinetic reflex (OKR). Mouse VO neurons, however, unlike their primate counterpart, were not modulated during OKR. Taken together, our results show that the integration of visual and vestibular information in the mouse vestibular nucleus is limited to a subpopulation of neurons which likely supports gaze stabilization for both VOR and OKR.

PMID: 17625061 [PubMed - indexed for MEDLINE]


69. Gene Expr Patterns. 2007 Aug;7(7):798-807. Epub 2007 May 26.

Expression of LHX3 and SOX2 during mouse inner ear development.

Hume CR, Bratt DL, Oesterle EC.

Department of Otolaryngology - Head and Neck Surgery, Virginia Merrill Bloedel Hearing Research Center, University of Washington, VMBHRC, CHDD, CD176, Box 357923, 1959 NE Pacific, Seattle, WA 98195, USA. hume@u.washington.edu

A cascade of transcription factors is believed to regulate the coordinate differentiation of primordial inner ear cells into the subtypes of hair cells and supporting cells. While candidate genes involved in this process have been identified, the temporal and spatial patterns of expression of many of these have not been carefully described during the extended period of inner ear development and functional maturation. We systematically examined the expression of two such transcription factors, LHX3 and SOX2, from the time of hair cell terminal mitoses into adulthood. We show that LHX3 is expressed specifically in auditory and vestibular hair cells soon after terminal mitoses and persists into the adult in vestibular hair cells. While SOX2 expression is widespread in the inner ear sensory epithelia prior to hair cell differentiation, it has a unique pattern of expression in the mature auditory and vestibular organs.

PMCID: PMC2043117 PMID: 17604700 [PubMed - indexed for MEDLINE]


70. BMC Neurosci. 2007 Jun 18;8:40.

The development of descending projections from the brainstem to the spinal cord in the fetal sheep.

Stockx EM, Anderson CR, Murphy SM, Cooke IR, Berger PJ.

Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia. elaine.stockx@med.monash.edu.au

BACKGROUND: Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to the marked change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus. CONCLUSION: The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord.

PMCID: PMC1919385 PMID: 17577416 [PubMed - indexed for MEDLINE]


71. J Vestib Res. 2006;16(4-5):179-86.

A critical period for the impact of vestibular sensation on ferret motor development.

Van Cleave S, Shall MS.

Department of Physical Therapy, Virginia Commonwealth University, Richmond, VA 23298-0224, USA.

Children with hearing deficits and hypofunctioning vestibular receptors frequently have delayed motor development. This study focuses on when the vestibular system needs to be active for normal motor behavior development and the maturation of the soleus muscle in the ferret. Both vestibular labyrinths were removed from ferrets at Postnatal day 10 (P10), P21, or P45 and the resulting data were compared with ferrets that had undergone a sham surgery at the same ages. The animals were sacrificed at P120 (young adult ferret). The resulting data from these ferrets revealed that standing and walking balance was significantly affected when the vestibular system was eliminated at or before P21. The soleus of P10 and P21 animals generally had smaller diameter muscle fibers and proportionally less type I Myosin Heavy Chain (MHC) and more type IIX MHC. The twitch contraction time of the soleus of the P21 group was significantly slower than the other groups. It appears that the vestibular system is important to motor and muscle fiber development in the ferret during the period before P21. The eyes are still closed at that age and all of the vestibular receptors are not fully mature. These findings imply a "critical period" for vestibular sensation and the development of a muscle that is important to standing balance.

PMCID: PMC2034323 PMID: 17538206 [PubMed - indexed for MEDLINE]


72. Pain Physician. 2007 May;10(3):467-72.

Hydrocodone use and sensorineural hearing loss.

Ho T, Vrabec JT, Burton AW.

Baylor College of Medicine, Houston, TX, USA.

BACKGROUND: The hydrocodone/acetaminophen combination is one of the most commonly used analgesic preparations. Isolated incidences of suspected association between hydrocodone abuse and rapidly progressive hearing loss have been reported. In this study, we describe the clinical characteristics of 5 patients presenting with progressive hearing loss and a history of hydrocodone use. METHODS: Patients presenting with rapidly progressive bilateral hearing loss who had a documented history of hydrocodone use were selected for the study. The presentation, audiologic findings, associated comorbidities, and treatment outcomes were reviewed. RESULTS: All patients displayed rapidly progressive sensorineural hearing loss without vestibular symptoms. Hearing loss was asymmetric in 3 patients at initial presentation, but progressed to profound loss, usually within months. Steroid treatment has no effect on the progression of the hearing loss. The admitted quantity of hydrocodone consumed ranged from 10 to 300 mg per day. Hepatitis C was the most common comorbidity, present in 60% of the patients. All patients underwent cochlear implantation with satisfactory results. CONCLUSIONS: The chronic use of hydrocodone can be associated with progressive sensorineural hearing loss. Successful auditory rehabilitation can be achieved with cochlear implantation. Genetic polymorphisms of drug metabolizing enzymes as well as associated comorbidities such as hepatitis C infection may be significant in the development of hydrocodone ototoxicity, though additional investigations are necessary.

PMID: 17525781 [PubMed - indexed for MEDLINE]


73. Braz J Otorhinolaryngol. 2007 Jan-Feb;73(1):100-5.

Otoneurologic findings in Type 1 Diabetes mellitus patients.

Rigon R, Rossi AG, Cóser PL.

Federal University of Santa Maria, Santa Maria, RS, Brazil. rafarigon@hotmail.com

Metabolic alterations, as they occur in Diabetes mellitus, have been mentioned in the development and maintenance of complaints related to the vestibular and auditory organs. AIM: To investigate the vestibular system in Type 1 Diabetic mellitus population. MATERIAL AND METHOD: The present study was developed with 19 individuals, being 10 females (52.6%) and 9 males (47.3%), with ages varying from 8 to 25 years old, with medical diagnosis of Type 1 Diabetes mellitus. For result comparison, a control group was selected with others 19 individuals, matching the study group in age and gender. The evaluation protocol encompassed interview, otoscopic inspection, dynamic and static balance evaluation, cerebellar tests and vectoelectronystagmographic evaluation. STUDY DESIGN: Clinical prospective. RESULTS: Alteration in the vectoelectronystagmographic evaluation were found in 36.84% (n=7) Type 1 Diabetes mellitus individuals, being 21.06% (n=4) Peripheral Deficiency Vestibular Syndrome and 15.79% (n=3) Peripheral Irritative Vestibular Syndrome. CONCLUSION: We conclude that Type 1 Diabetes mellitus individuals can have their vestibular organ affected, even if there are no otoneurologic complaints.

PMID: 17505607 [PubMed - indexed for MEDLINE]


74. Am J Hum Genet. 2007 Jun;80(6):1076-89. Epub 2007 Apr 24.

A mutation in CCDC50, a gene encoding an effector of epidermal growth factor-mediated cell signaling, causes progressive hearing loss.

Modamio-Hoybjor S, Mencia A, Goodyear R, del Castillo I, Richardson G, Moreno F, Moreno-Pelayo MA.

Unidad de Genetica Molecular, Hospital Ramon y Cajal, Madrid, Spain.

We previously mapped a novel autosomal dominant deafness locus, DFNA44, by studying a family with postlingual, progressive, nonsyndromic hearing loss. We report here on the identification of a mutation in CCDC50 as the cause of hearing loss in the family. CCDC50 encodes Ymer, an effector of epidermal growth factor (EGF)-mediated cell signaling that is ubiquitously expressed in different organs and has been suggested to inhibit down-regulation of the EGF receptor. We have examined its expression pattern in mouse inner ear. Western blotting and cell transfection results indicate that Ymer is a soluble, cytoplasmic protein, and immunostaining shows that Ymer is expressed in a complex spatiotemporal pattern during inner ear development. In adult inner ear, the expression of Ymer is restricted to the pillar cells of the cochlea, the stria vascularis, and the vestibular sensory epithelia, where it shows spatial overlap with the microtubule-based cytoskeleton. In dividing cells, Ymer colocalizes with microtubules of the mitotic apparatus. We suggest that DFNA44 hearing loss may result from a time-dependent disorganization of the microtubule-based cytoskeleton in the pillar cells and stria vascularis of the adult auditory system.

PMCID: PMC1867096 PMID: 17503326 [PubMed - indexed for MEDLINE]


75. Int J Dev Biol. 2007;51(3):201-9.

Cell proliferation during the early compartmentalization of the Xenopus laevis inner ear.

Quick QA, Serrano EE.

Department of Biology, New Mexico State University, Las Cruces, New Mexico 88033, USA.

The auditory and vestibular endorgans of the inner ear which are essential for the senses of hearing and balance form early during development when the otocyst undergoes a period of rapid growth and compartmentalization. Here we show the spatial and temporal patterns of proliferating cells in the Xenopus laevis inner ear as this organ develops from an otic vesicle at stage 31 until stage 47, an age at which compartmentalization and the initial appearance of sensory structures are evident. Sites of new cell production were identified in specimens at stages 31, 37, 42, 45 and 47 using immunohistochemical methods to detect bromodeoxyuridine (BrdU) incorporation three hours after exposure to this thymidine analogue. Cells undergoing terminal mitosis at stages 37, 42 and 45 were detected by exposing specimens at these stages to BrdU and permitting development to proceed until stage 47. Our results show that while newly replicating cells are uniformly distributed throughout the stage 31 otic vesicle, they are spatially restricted in stages 37 through 45, with few dividing cells visible in the central patches of the emerging sensory epithelia. In contrast, no clear proliferative pattern was discerned at stage 47. BrdU-positive cells that had undergone terminal mitosis at stage 37, 42 and 45 were detected in the central regions of nascent sensory epithelia at stage 47. These findings are consistent with a developmental mechanism in which cells undergoing terminal mitosis during early X. laevis stages contribute to sensory epithelia and in which cell mixing and migration are features of inner ear compartmentalization.

PMID: 17486540 [PubMed - indexed for MEDLINE]


76. Development. 2007 May;134(9):1713-22. Epub 2007 Mar 29.

Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear.

Bok J, Dolson DK, Hill P, Rüther U, Epstein DJ, Wu DK.

National Institute on Deafness and Other Communication Disorders, Rockville, MD 20850, USA.

Organization of the vertebrate inner ear is mainly dependent on localized signals from surrounding tissues. Previous studies demonstrated that sonic hedgehog (Shh) secreted from the floor plate and notochord is required for specification of ventral (auditory) and dorsal (vestibular) inner ear structures, yet it was not clear how this signaling activity is propagated. To elucidate the molecular mechanisms by which Shh regulates inner ear development, we examined embryos with various combinations of mutant alleles for Shh, Gli2 and Gli3. Our study shows that Gli3 repressor (R) is required for patterning dorsal inner ear structures, whereas Gli activator (A) proteins are essential for ventral inner ear structures. A proper balance of Gli3R and Gli2/3A is required along the length of the dorsoventral axis of the inner ear to mediate graded levels of Shh signaling, emanating from ventral midline tissues. Formation of the ventral-most otic region, the distal cochlear duct, requires robust Gli2/3A function. By contrast, the formation of the proximal cochlear duct and saccule, which requires less Shh signaling, is achieved by antagonizing Gli3R. The dorsal vestibular region requires the least amount of Shh signaling in order to generate the correct dose of Gli3R required for the development of this otic region. Taken together, our data suggest that reciprocal gradients of GliA and GliR mediate the responses to Shh signaling along the dorsoventral axis of the inner ear.

PMID: 17395647 [PubMed - indexed for MEDLINE]


77. J Neurosci. 2007 Mar 21;27(12):3139-47.

Asymmetric distribution of prickle-like 2 reveals an early underlying polarization of vestibular sensory epithelia in the inner ear.

Deans MR, Antic D, Suyama K, Scott MP, Axelrod JD, Goodrich LV.

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Vestibular hair cells have a distinct planar cell polarity (PCP) manifest in the morphology of their stereocilia bundles and the asymmetric localization of their kinocilia. In the utricle and saccule the hair cells are arranged in an orderly array about an abrupt line of reversal that separates fields of cells with opposite polarity. We report that the putative PCP protein Prickle-like 2 (Pk2) is distributed in crescents on the medial sides of vestibular epithelial cells before the morphological polarization of hair cells. Despite the presence of a line of polarity reversal, crescent position is not altered between hair cells of opposite polarity. Frizzled 6 (Fz6), a second PCP protein, is distributed opposite Pk2 along the lateral side of vestibular support cells. Similar to Pk2, the subcellular localization of Fz6 does not differ between cells located on opposite sides of the line of reversal. In addition, in Looptail/Van Gogh-like2 mutant mice Pk2 is distributed asymmetrically at embryonic day 14.5 (E14.5), but this localization is not coordinated between adjacent cells, and the crescents subsequently are lost by E18.5. Together, these results support the idea that a conserved PCP complex acts before stereocilia bundle development to provide an underlying polarity to all cells in the vestibular epithelia and that cells on either side of the line of reversal are programmed to direct the kinocilium in opposite directions with respect to the polarity axis defined by PCP protein distribution.

PMID: 17376975 [PubMed - indexed for MEDLINE]


78. J Physiol. 2007 Jun 15;581(Pt 3):1101-12. Epub 2007 Mar 1.

Developmental changes in potassium currents at the rat calyx of Held presynaptic terminal.

Nakamura Y, Takahashi T.

Department of Neurophysiology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

During early postnatal development, the calyx of Held synapse in the auditory brainstem of rodents undergoes a variety of morphological and functional changes. Among ionic channels expressed in the calyx, voltage-dependent K+ channels regulate transmitter release by repolarizing the nerve terminal. Here we asked whether voltage-dependent K+ channels in calyceal terminals undergo developmental changes, and whether they contribute to functional maturation of this auditory synapse. From postnatal day (P) 7 to P14, K+ currents became larger and faster in activation kinetics, but did not change any further to P21. Likewise, presynaptic action potentials became shorter in duration from P7 to P14 and remained stable thereafter. The density of presynaptic K+ currents, assessed from excised patch recording and whole-cell recordings with reduced [K+]i, increased by 2-3-fold during the second postnatal week. Pharmacological isolation of K+ current subtypes using tetraethylammonium (1 mM) and margatoxin (10 nM) revealed that the density of Kv3 and Kv1 currents underwent a parallel increase, and their activation kinetics became accelerated by 2-3-fold. In contrast, BK currents, isolated using iberiotoxin (100 nM), showed no significant change during the second postnatal week. Pharmacological block of Kv3 or Kv1 channels at P7 and P14 calyceal terminals indicated that the developmental changes of Kv3 channels contribute to the establishment of reliable action potential generation at high frequency, whereas those of Kv1 channels contribute to stabilizing the nerve terminal. We conclude that developmental changes in K+ currents in the nerve terminal contribute to maturation of high-fidelity fast synaptic transmission at this auditory relay synapse.

PMCID: PMC2170855 PMID: 17331991 [PubMed - indexed for MEDLINE]


79. J Neurosci. 2007 Feb 28;27(9):2163-75.

A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function.

Schwander M, Sczaniecka A, Grillet N, Bailey JS, Avenarius M, Najmabadi H, Steffy BM, Federe GC, Lagler EA, Banan R, Hice R, Grabowski-Boase L, Keithley EM, Ryan AF, Housley GD, Wiltshire T, Smith RJ, Tarantino LM, Müller U.

Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, California 92037, USA.

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.

PMID: 17329413 [PubMed - indexed for MEDLINE]


80. Arch Otolaryngol Head Neck Surg. 2007 Feb;133(2):162-8.

The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct.

Madden C, Halsted M, Meinzen-Derr J, Bardo D, Boston M, Arjmand E, Nishimura C, Yang T, Benton C, Das V, Smith R, Choo D, Greinwald J.

Department of Audiovestibular Medicine, Manchester Royal Infirmary, Manchester, England.

Erratum in:

   Arch Otolaryngol Head Neck Surg. 2007 Jun;133(6):607.

OBJECTIVE: To correlate genetic and audiometric findings with a detailed radiologic analysis of the temporal bone in patients with enlarged vestibular aqueduct (EVA) to ascertain the contribution of SLC26A4 gene mutations to this phenotype. DESIGN: A retrospective review of patients with EVA identified in a database of pediatric hearing-impaired patients. SETTING: A tertiary care pediatric referral center. PATIENTS: Seventy-one children with EVA and screening results for SLC26A4 mutations. MAIN OUTCOME MEASURES: Genetic screening results, audiometric thresholds, and radiographic temporal bone measurements. RESULTS: Seventy-one children with EVA were screened for SLC26A4 mutations. Mutations were found in 27% of children overall, while only 8% had biallelic mutations. The mean initial pure-tone average (PTA) was 59 dB; the mean final PTA was 67 dB. A bilateral EVA was found in 48 (67%) of the children; a unilateral EVA was found in 23 (33%). Progressive hearing loss (in at least 1 ear) was seen in 29 (41%) of the patients. The strongest genotype-phenotype interaction was seen in children with a bilateral EVA. Among children with SLC26A4 mutations, there was a significantly wider vestibular aqueduct at the midpoint and a wider vestibule width (P < .05) than in children without the mutation. Among patients with a bilateral EVA, children with any SLC26A4 mutation were more likely to have a more severe final PTA (64 dB vs 32 dB), larger midpoint measurement (2.1 vs 1.1 mm), and larger operculum measurement (3.0 vs 2.0 mm) than those without the mutation in their better-hearing ear (P < .05). CONCLUSIONS: In a population of pediatric patients with an EVA and hearing loss, SLC26A4 mutations are a contributor to the phenotype. Our data suggest that other genetic factors also have important contributions to this phenotype. The presence of an abnormal SLC26A4 allele, even in the heterozygous state, was associated with greater enlargement of the vestibular aqueduct, abnormal development of the vestibule, and possibly a stable hearing outcome.

PMID: 17309986 [PubMed - indexed for MEDLINE]


81. Sheng Li Xue Bao. 2007 Feb 25;59(1):71-8.

Changes of amino acid concentrations in the rat medial vestibular nucleus following unilateral labyrinthectomy.

Yu HL, An Y, Jiang HY, Jin QH, Jin YZ.

Department of Pharmacology, Yanbian University College of Medicine, Yanji 133000, China.

To understand the neurochemical mechanisms underlying the vestibular compensation, we determined the levels of amino acids such as aspartate, glutamate, glutamine, glycine, taurine, alanine in the medial vestibular nucleus (MVN) following unilateral labyrinthectomy (UL), by using in vivo brain microdialysis and high-performance liquid chromatography technique. Rats were pretreated by infusing 2% lidocaine 1.2 mL or 10 mg arsanilic acid into the tympanic cavity to obstruct uni-periphery vestibular organ, and then the levels of amino acids were determined in MVN of normal control and ipsilateral or contralateral lesional (ipsi-/contra-lesional) rats. In the control experiment, the levels of aspartate, glutamate, glutamine, glycine, taurine, and alanine were (6.15 +/- 0.59), (18.13 +/- 1.21), (33.73 +/- 1.67), (9.26 +/- 0.65), (9.56 +/- 0.77) and (10.07 +/- 0.83) pmol/8 muL sample, respectively. The concentrations of aspartate and glutamate decreased, while the concentration of taurine increased in the ipsi-lesional MVN of rats 10 min after infusing 2% lidocaine into middle ear to obstruct uni-periphery vestibular organ. Whereas the concentration of glutamate increased, the concentrations of glycine and alanine decreased in the contra-lesional MVN, accompanied by imbalances of glutamate, glycine and alanine in the bilateral nuclei. In contrast, the levels of glutamate and alanine decreased, the level of glutamine increased in the ipsi-lesional MVN, and the level of glutamate decreased in the contra-lesional MVN of rats 2 weeks after infusing 10 mg arsanilic acid into the tympanic cavity to obstruct uni-periphery vestibular organ. Furthermore, the level of glutamine in the ipsi-lesional MVN was obviously higher than that in the contra-lesional MVN. These results demonstrate that an imbalance of different amino acids appeared in bilateral MVN after UL, and this imbalance decreased after the development of vestibular compensation. Whereas the imbalance of glutamine release in bilateral nuclei appeared after vestibular compensation.

PMID: 17294045 [PubMed - in process]


82. Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2997-3002. Epub 2007 Feb 9.

Differentiation of ES cells into cerebellar neurons.

Salero E, Hatten ME.

Laboratory of Developmental Neurobiology, The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399, USA.

The neuronal circuits of the cerebellar cortex are essential for motor and sensory learning, associative memory formation, and the vestibular ocular reflex. In children and young adults, tumors of the granule cell, the medulloblastomas, represent 40% of brain tumors. We report the differentiation of E14 ES cells into mature granule neurons by sequential treatment with secreted factors (WNT1, FGF8, and RA) that initiate patterning in the cerebellar region of the neural tube, bone morphogenic proteins (BMP6/7 and GDF7) that induce early granule cell progenitor markers (MATH1, MEIS1, ZIC1), mitogens (SHH, JAG1) that control proliferation and induce additional granule cell markers (Cyclin D2, PAX2/6), and culture in glial-conditioned medium to induce markers of mature granule neurons (GABAalpha(6)r), including ZIC2, a unique marker for granule neurons. Differentiated ES cells formed classic "T-shaped" granule cell axons in vitro, and implantation of differentiated Pde1c-Egfp-BAC transgenic ES cells into the external granule cell layer of neonatal mice resulted in the extension of parallel fibers, migration across the molecular layer, incorporation into the internal granule cell layer, and extension of short dendrites, typical of young granule cells forming synaptic connections with afferent mossy fibers. These results underscore the utility of treating ES cells with local, inductive signals that regulate CNS neuronal development in vivo as a strategy for cell replacement therapy of defined neuronal populations.

PMCID: PMC1796781 PMID: 17293457 [PubMed - indexed for MEDLINE]


83. Brain Res. 2007 Mar 30;1139:117-25. Epub 2007 Jan 8.

Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia.

Rocha-Sanchez SM, Morris KA, Kachar B, Nichols D, Fritzsch B, Beisel KW.

Department of Oral Biology, Creighton University School of Dentistry, 2500 California Plaza, Omaha, NE 68178, USA. ssanchez@creighton.edu

Sensory signal transduction of the inner ear afferent neurons and hair cells (HCs) requires numerous ionic conductances. The KCNQ4 voltage-gated M-type potassium channel is thought to set the resting membrane potential in cochlear HCs. Here we describe the spatiotemporal expression patterns of Kcnq4 and the associated alternative splice forms in the HCs of vestibular labyrinth. Whole mount immunodetection, qualitative and quantitative RT-PCR were performed to characterize the expression patterns of Kcnq4 transcripts and proteins. A topographical expression and upregulation of Kcnq4 during development was observed and indicated that Kcnq4 is not restricted to either a specific vestibular structure or cell type, but is present in afferent calyxes, vestibular ganglion neurons, and both type I and type II HCs. Of the four alternative splice variants, Kcnq4_v1 transcripts were the predominant form in the HCs, while Kcnq4_v3 was the major variant in the vestibular neurons. Differential quantitative expression of Kcnq4_v1 and Kcnq4_v3 were respectively detected in the striolar and extra-striolar regions of the utricle and saccule. Analysis of gerbils and rats yielded results similar to those obtained in mice, suggesting that the spatiotemporal expression pattern of Kcnq4 in the vestibular system is conserved among rodents. Analyses of vestibular HCs of Bdnf conditional mutant mice, which are devoid of any innervation, demonstrate that regulation of Kcnq4 expression in vestibular HCs is independent of innervation.

PMCID: PMC1858668 PMID: 17292869 [PubMed - indexed for MEDLINE]


84. J Neurosci. 2007 Feb 7;27(6):1474-8.

Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.

Herr DR, Grillet N, Schwander M, Rivera R, Müller U, Chun J.

Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, La Jolla, California 92037, USA.

Hearing requires the transduction of vibrational forces by specialized epithelial cells in the cochlea known as hair cells. The human ear contains a finite number of terminally differentiated hair cells that, once lost by noise-induced damage or toxic insult, can never be regenerated. We report here that sphingosine 1-phosphate (S1P) signaling, mainly via activation of its cognate receptor S1P2, is required for the maintenance of vestibular and cochlear hair cells in vivo. Two S1P receptors, S1P2 and S1P3, were found to be expressed in the cochlea by reverse transcription-PCR and in situ hybridization. Mice that are null for both these receptors uniformly display progressive cochlear and vestibular defects with hair cell loss, resulting in complete deafness by 4 weeks of age and, with complete penetrance, balance defects of increasing severity. This study reveals the previously unknown role of S1P signaling in the maintenance of cochlear and vestibular integrity and suggests a means for therapeutic intervention in degenerative hearing loss.

PMID: 17287522 [PubMed - indexed for MEDLINE]


85. J Biol Chem. 2007 Apr 6;282(14):10690-6. Epub 2007 Feb 6.

Deafness and stria vascularis defects in S1P2 receptor-null mice.

Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington D, Bolz SS, Friedman TB, Hla T, Proia RL.

Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1821, USA.

The S1P(2) receptor is a member of a family of G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. The receptor is widely expressed and linked to multiple G protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated that S1P(2) receptor expression is essential for proper functioning of the auditory and vestibular systems. Auditory brainstem response analysis revealed that S1P(2) receptor-null mice were deaf by one month of age. These null mice exhibited multiple inner ear pathologies. However, some of the earliest cellular lesions in the cochlea were found within the stria vascularis, a barrier epithelium containing the primary vasculature of the inner ear. Between 2 and 4 weeks after birth, the basal and marginal epithelial cell barriers and the capillary bed within the stria vascularis of the S1P(2) receptor-null mice showed markedly disturbed structures. JTE013, an S1P(2) receptor-specific antagonist, blocked the S1P-induced vasoconstriction of the spiral modiolar artery, which supplies blood directly to the stria vascularis and protects its capillary bed from high perfusion pressure. Vascular disturbance within the stria vascularis is a potential mechanism that leads to deafness in the S1P(2) receptor-null mice.

PMID: 17284444 [PubMed - indexed for MEDLINE]


86. Conf Proc IEEE Eng Med Biol Soc. 2005;7:7380-5.

Electrical stimulation to restore vestibular function development of a 3-d vestibular prosthesis.

Della Santina C, Migliaccio A, Patel A.

Departments of Otolaryngology-Head & Neck Surgery and Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Patients who fail to compensate for bilateral loss of vestibular sensory function are disabled by disequilibrium and illusory movement of the visual field during head movement. An implantable prosthesis that restores vestibular sensation could significantly improve quality of life for these patients. To be effective, such a device should encode head rotation in all 3 dimensions. We describe the 3-dimensional angular vestibulo-ocular reflex of normal chinchillas and vestibular-deficient chinchillas undergoing functional electrical stimulation of the vestibular nerve. We also describe the design and fabrication of a head-mounted, 8 electrode vestibular prosthesis that encodes head movement in 3 dimensions.

PMCID: PMC2767263 PMID: 17281986 [PubMed - in process]


87. Mol Cell Neurosci. 2007 Mar;34(3):468-80. Epub 2007 Feb 2.

Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice.

Karavanova I, Vasudevan K, Cheng J, Buonanno A.

Section on Molecular Neurobiology, National Institute of Child Health and Human Development, Bldg. 35, Room 2C-1000, 35 Lincoln Drive, National Institutes of Health, Bethesda, MD 20892, USA.

NMDA receptor "knock-in" mice were generated by inserting the nuclear beta-galactosidase reporter at the NR2C subunit translation initiation site. Novel cell types and dynamic patterns of NR2C expression were identified using these mice, which were unnoticed before because reagents that specifically recognize NR2C-containing receptors are non-existent. We identified a transition zone from NR2C-expressing neurons to astrocytes in an area connecting the retrosplenial cortex and hippocampus. We demonstrate that NR2C is expressed in a subset of S100beta-positive/GFAP-negative glial cells in the striatum, olfactory bulb and cerebral cortex. We also demonstrate novel areas of neuronal expression such as retrosplenial cortex, thalamus, pontine and vestibular nuclei. In addition, we show that during cerebellar development NR2C is expressed in transient caudal-rostral gradients and parasagittal bands in subsets of granule cells residing in the internal granular layer, further demonstrating heterogeneity of granule neurons. These results point to novel functions of NR2C-containing NMDA receptors.

PMCID: PMC1855159 PMID: 17276696 [PubMed - indexed for MEDLINE]


88. Development. 2007 Feb;134(4):647-58.

Tissue/planar cell polarity in vertebrates: new insights and new questions.

Wang Y, Nathans J.

Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ywang@mail.jhmi.edu

This review focuses on the tissue/planar cell polarity (PCP) pathway and its role in generating spatial patterns in vertebrates. Current evidence suggests that PCP integrates both global and local signals to orient diverse structures with respect to the body axes. Interestingly, the system acts on both subcellular structures, such as hair bundles in auditory and vestibular sensory neurons, and multicellular structures, such as hair follicles. Recent work has shown that intriguing connections exist between the PCP-based orienting system and left-right asymmetry, as well as between the oriented cell movements required for neural tube closure and tubulogenesis. Studies in mice, frogs and zebrafish have revealed that similarities, as well as differences, exist between PCP in Drosophila and vertebrates.

PMID: 17259302 [PubMed - indexed for MEDLINE]


89. J Neurosci. 2007 Jan 24;27(4):782-90.

Multiple mechanosensory modalities influence development of auditory function.

Horowitz SS, Tanyu LH, Simmons AM.

Department of Psychology, Brown University, Providence, Rhode Island 02912, USA.

Sensory development can be dependent on input from multiple modalities. During metamorphic development, ranid frogs exhibit rapid reorganization of pathways mediating auditory, vestibular, and lateral line modalities as the animal transforms from an aquatic to an amphibious form. Here we show that neural sensitivity to the underwater particle motion component of sound follows a different developmental trajectory than that of the pressure component. Throughout larval stages, cells in the medial vestibular nucleus show best frequencies to particle motion in the range from 15 to 65 Hz, with displacement thresholds of <10 mum. During metamorphic climax, best frequencies significantly increase, and sensitivity to lower-frequency (<25 Hz) stimuli tends to decline. These findings suggest that continued sensitivity to particle motion may compensate for the considerable loss of sensitivity to pressure waves observed during the developmental deaf period. Transport of a lipophilic dye from peripheral end organs to the dorsal medulla shows that fibers from the saccule in the inner ear and from the anterior lateral line both terminate in the medial vestibular nucleus. Saccular projections remain stable across larval development, whereas lateral line projections degenerate during metamorphic climax. Sensitivity to particle motion may be based on multimodal input early in development and on saccular input alone during the transition to amphibious life.

PMID: 17251417 [PubMed - indexed for MEDLINE]


90. J Anat. 2007 Jan;210(1):78-88.

Neurotrophin and Trk neurotrophin receptors in the inner ear of Salmo salar and Salmo trutta.

Catania S, Germanà A, Cabo R, Ochoa-Erena FJ, Guerrera MC, Hannestad J, Represa J, Vega JA.

Dipartimento di Morfologia, Biochimica, Fisiologia e Produzione Animale, Università di Messina, Italy.

Neurotrophins (NTs) and their signal transducing Trk receptors play a critical role in the development and maintenance of specific neuronal populations in the nervous system of higher vertebrates. They are responsible for the innervation of the inner ear cochlear and vestibular sensory epithelia. Neurotrophins and Trks are also present in teleosts but their distribution in the inner ear is unknown. Thus, in the present study, we used Western-blot analysis and immunohistochemistry to investigate the expression and cell localization of both NTs and Trk receptors in the inner ear of alevins of Salmo salar and Salmo trutta. Western-blot analysis revealed the occurrence of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor (NGF), as well as all three Trk receptors, i.e. TrkA, TrkB and TrkC, the estimated molecular weights of which were similar to those expected for mammals. Specific immunoreactivity for neurotrophins was detected mainly in the sensory epithelia. In particular, BDNF immunoreactivity was found in the maculae of the utricle and saccule, whereas NT-3 immunoreactivity was present in the sensory epithelium of the cristae ampullaris. As a rule the sensory epithelia of the inner ear lacked immunoreactivity for Trks, thus excluding possible mechanisms of autocrinia and/or paracrinia. By contrast, overlapping subpopulations of neurons in the statoacoustic ganglion expressed TrkA (about 15%), TrkB (about 65%) and TrkC (about 45%). The present results demonstrate that, as in mammals and birds, the inner ear of teleosts expresses the components of the neurotrophin-Trk system, but their roles remain to be elucidated.

PMCID: PMC2100255 PMID: 17229285 [PubMed - indexed for MEDLINE]


91. J Assoc Res Otolaryngol. 2007 Mar;8(1):18-31. Epub 2006 Dec 14.

Differential distribution of stem cells in the auditory and vestibular organs of the inner ear.

Oshima K, Grimm CM, Corrales CE, Senn P, Martinez Monedero R, Géléoc GS, Edge A, Holt JR, Heller S.

Department of Otolaryngology-Head & Neck Surgery, Stanford University School of Medicine, 801 Welch Road, Stanford, CA 94305-5739, USA.

The adult mammalian cochlea lacks regenerative capacity, which is the main reason for the permanence of hearing loss. Vestibular organs, in contrast, replace a small number of lost hair cells. The reason for this difference is unknown. In this work we show isolation of sphere-forming stem cells from the early postnatal organ of Corti, vestibular sensory epithelia, the spiral ganglion, and the stria vascularis. Organ of Corti and vestibular sensory epithelial stem cells give rise to cells that express multiple hair cell markers and express functional ion channels reminiscent of nascent hair cells. Spiral ganglion stem cells display features of neural stem cells and can give rise to neurons and glial cell types. We found that the ability for sphere formation in the mouse cochlea decreases about 100-fold during the second and third postnatal weeks; this decrease is substantially faster than the reduction of stem cells in vestibular organs, which maintain their stem cell population also at older ages. Coincidentally, the relative expression of developmental and progenitor cell markers in the cochlea decreases during the first 3 postnatal weeks, which is in sharp contrast to the vestibular system, where expression of progenitor cell markers remains constant or even increases during this period. Our findings indicate that the lack of regenerative capacity in the adult mammalian cochlea is either a result of an early postnatal loss of stem cells or diminishment of stem cell features of maturing cochlear cells.

PMCID: PMC2538418 PMID: 17171473 [PubMed - indexed for MEDLINE]


92. Braz J Biol. 2006 Aug;66(3):907-17.

Notes on the biology of Trypoxylon (Trypargilum) opacum Brèthes (Hymenoptera; Crabronidae) in Southern Brazil.

Buschini ML, Wolff LL.

Depto de Biologia, UNICENTRO, Guarapuava, PR, Brazil. isatunes@yahoo.com.br

The present study investigated the abundance, seasonality and various life-history traits of Trypoxylon (Trypargilum) opacum. Using trap-nests, 320 nests of T. opacum were collected in the Parque Municipal das Araucárias in Southern Brazil (25 degrees 23' 36" S and 51 degrees 27' 19" W) over a 3 year period. Nesting was more frequent during the warm season. Nests consisted of a linear series of 1 to 8 brood cells separated by mud partitions, usually followed by an empty vestibular cell and final-closure mud plug. Brood cells were most commonly provisioned with spiders of the family Araneidae. Sex-ratio was strongly female biased, 3.4:1 females:males. Natural enemies attacking nests T. opacum included chrysidids, ichneumonids, sarcophagids, bombyliids and ants.

PMID: 17119839 [PubMed - indexed for MEDLINE]


93. Dev Dyn. 2007 Jan;236(1):306-13.

Comparative analysis of Gata3 and Gata2 expression during chicken inner ear development.

Lilleväli K, Haugas M, Pituello F, Salminen M.

Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

The inner ear is a complex sensory organ with hearing and balance functions. Gata3 and Gata2 are expressed in the inner ear, and to gain more insight into their roles in otic development, we made a detailed expression analysis in chicken embryos. At early stages, their expression was highly overlapping. At later stages, Gata2 expression became prominent in vestibular and cochlear nonsensory epithelia. In contrast to Gata2, Gata3 was mainly expressed in the developing sensory epithelia, reflecting the importance of this factor in the sensory-neural development of the inner ear. While the later expression patterns of both Gata3 and Gata2 were highly conserved between chicken and mouse, important differences were observed especially with Gata3 during early otic development, providing indications of divergent molecular control during placode invagination in mice and chickens. We also found indications that the regulatory hierarchy observed in mouse, where Gata3 is upstream of Gata2 and Fgf10, could be conserved in chicken.

PMID: 17103399 [PubMed - indexed for MEDLINE]


94. J Assoc Res Otolaryngol. 2006 Dec;7(4):383-98. Epub 2006 Oct 31.

Electrophysiological validation of a human prototype auditory midbrain implant in a guinea pig model.

Lenarz M, Lim HH, Patrick JF, Anderson DJ, Lenarz T.

Otorhinolaryngology Department, Medical University of Hannover, Hannover, Lower Saxony 30625, Germany.

The auditory midbrain implant (AMI) is a new treatment for hearing restoration in patients with neural deafness or surgically inaccessible cochleae who cannot benefit from cochlear implants (CI). This includes neurofibromatosis type II (NF2) patients who, due to development and/or removal of vestibular schwannomas, usually experience complete damage of their auditory nerves. Although the auditory brainstem implant (ABI) provides sound awareness and aids lip-reading capabilities for these NF2 patients, it generally only achieves hearing performance levels comparable with a single-channel CI. In collaboration with Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which is designed for electrical stimulation along the well-defined tonotopic gradient of the inferior colliculus central nucleus (ICC). Considering that better speech perception and hearing performance has been correlated with a greater number of discriminable frequency channels of information available, the ability of the AMI to effectively activate discrete frequency regions within the ICC may enable better hearing performance than achieved by the ABI. Therefore, the goal of this study was to investigate if our AMI array could achieve low-threshold, frequency-specific activation within the ICC, and whether the levels for ICC activation via AMI stimulation were within safe limits for human application. We electrically stimulated different frequency regions within the ICC via the AMI array and recorded the corresponding neural activity in the primary auditory cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs. Based on our results, AMI stimulation achieves lower thresholds and more localized, frequency-specific activation than CI stimulation. Furthermore, AMI stimulation achieves cortical activation with current levels that are within safe limits for central nervous system stimulation. This study confirms that our AMI design is sufficient for ensuring safe and effective activation of the ICC, and warrants further studies to translate the AMI into clinical application.

PMCID: PMC2504634 PMID: 17075701 [PubMed - indexed for MEDLINE]


95. J Neurophysiol. 2007 Feb;97(2):1684-704. Epub 2006 Oct 25.

Developmental changes in two voltage-dependent sodium currents in utricular hair cells.

Wooltorton JR, Gaboyard S, Hurley KM, Price SD, Garcia JL, Zhong M, Lysakowski A, Eatock RA.

Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.

Two kinds of sodium current (I(Na)) have been separately reported in hair cells of the immature rodent utricle, a vestibular organ. We show that rat utricular hair cells express one or the other current depending on age (between postnatal days 0 and 22, P0-P22), hair cell type (I, II, or immature), and epithelial zone (striola vs. extrastriola). The properties of these two currents, or a mix, can account for descriptions of I(Na) in hair cells from other reports. The patterns of Na channel expression during development suggest a role in establishing the distinct synapses of vestibular hair cells of different type and epithelial zone. All type I hair cells expressed I(Na,1), a TTX-insensitive current with a very negative voltage range of inactivation (midpoint: -94 mV). I(Na,2) was TTX sensitive and had less negative voltage ranges of activation and inactivation (inactivation midpoint: -72 mV). I(Na,1) dominated in the striola at all ages, but current density fell by two-thirds after the first postnatal week. I(Na,2) was expressed by 60% of hair cells in the extrastriola in the first week, then disappeared. In the third week, all type I cells and about half of type II cells had I(Na,1); the remaining cells lacked sodium current. I(Na,1) is probably carried by Na(V)1.5 subunits based on biophysical and pharmacological properties, mRNA expression, and immunoreactivity. Na(V)1.5 was also localized to calyx endings on type I hair cells. Several TTX-sensitive subunits are candidates for I(Na,2).

PMID: 17065252 [PubMed - indexed for MEDLINE]


96. J Neurosci. 2006 Oct 4;26(40):10253-69.

M-like K+ currents in type I hair cells and calyx afferent endings of the developing rat utricle.

Hurley KM, Gaboyard S, Zhong M, Price SD, Wooltorton JR, Lysakowski A, Eatock RA.

The Bobby R. Alford Department of Otorhinolaryngology, Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.

Type I vestibular hair cells have large K+ currents that, like neuronal M currents, activate negative to resting potential and are modulatable. In rodents, these currents are acquired postnatally. In perforated-patch recordings from rat utricular hair cells, immature hair cells [younger than postnatal day 7 (P7)] had a steady-state K+ conductance (g(-30)) with a half-activation voltage (V1/2) of -30 mV. The size and activation range did not change in maturing type II cells, but, by P16, type I cells had added a K conductance that was on average fourfold larger and activated much more negatively. This conductance may comprise two components: g(-60) (V1/2 of -60 mV) and g(-80) (V1/2 of -80 mV). g(-80) washed out during ruptured patch recordings and was blocked by a protein kinase inhibitor. M currents can include contributions from KCNQ and ether-a-go-go-related (erg) channels. KCNQ and erg channel blockers both affected the K+ currents of type I cells, with KCNQ blockers being more potent at younger than P7 and erg blockers more potent at older than P16. Single-cell reverse transcription-PCR and immunocytochemistry showed expression of KCNQ and erg subunits. We propose that KCNQ channels contribute to g(-30) and g(-60) and erg subunits contribute to g(-80). Type I hair cells are contacted by calyceal afferent endings. Recordings from dissociated calyces and afferent endings revealed large K+ conductances, including a KCNQ conductance. Calyx endings were strongly labeled by KCNQ4 and erg1 antisera. Thus, both hair cells and calyx endings have large M-like K+ conductances with the potential to control the gain of transmission.

PMID: 17021181 [PubMed - indexed for MEDLINE]


97. J Neurosci. 2006 Oct 4;26(40):10188-98.

The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function.

Gagnon LH, Longo-Guess CM, Berryman M, Shin JB, Saylor KW, Yu H, Gillespie PG, Johnson KR.

The Jackson Laboratory, Bar Harbor, Maine 04609, USA.

Although CLIC5 is a member of the chloride intracellular channel protein family, its association with actin-based cytoskeletal structures suggests that it may play an important role in their assembly or maintenance. Mice homozygous for a new spontaneous recessive mutation of the Clic5 gene, named jitterbug (jbg), exhibit impaired hearing and vestibular dysfunction. The jbg mutation is a 97 bp intragenic deletion that causes skipping of exon 5, which creates a translational frame shift and premature stop codon. Western blot and immunohistochemistry results confirmed the predicted absence of CLIC5 protein in tissues of jbg/jbg mutant mice. Histological analysis of mutant inner ears revealed dysmorphic stereocilia and progressive hair cell degeneration. In wild-type mice, CLIC5-specific immunofluorescence was detected in stereocilia of both cochlear and vestibular hair cells and also along the apical surface of Kolliker's organ during cochlear development. Refined immunolocalization in rat and chicken vestibular hair cells showed that CLIC5 is limited to the basal region of the hair bundle, similar to the known location of radixin. Radixin immunostaining appeared reduced in hair bundles of jbg mutant mice. By mass spectrometry and immunoblotting, CLIC5 was shown to be expressed at high levels in stereocilia of the chicken utricle, in an approximate 1:1 molar ratio with radixin. These results suggest that CLIC5 associates with radixin in hair cell stereocilia and may help form or stabilize connections between the plasma membrane and the filamentous actin core.

PMID: 17021174 [PubMed - indexed for MEDLINE]


98. Dev Dyn. 2006 Nov;235(11):3026-38.

Zebrafish pax5 regulates development of the utricular macula and vestibular function.

Kwak SJ, Vemaraju S, Moorman SJ, Zeddies D, Popper AN, Riley BB.

Biology Department, Texas A&M University, College Station, Texas, USA.

The zebrafish otic vesicle initially forms with only two sensory epithelia, the utricular and saccular maculae, which primarily mediate vestibular and auditory function, respectively. Here, we test the role of pax5, which is preferentially expressed in the utricular macula. Morpholino knockdown of pax5 disrupts vestibular function but not hearing. Neurons of the statoacoustic ganglion (SAG) develop normally. Utricular hair cells appear to form normally but a variable number subsequently undergo apoptosis and are extruded from the otic vesicle. Dendrites of the SAG persist in the utricle but become disorganized after hair cell loss. Hair cells in the saccule develop and survive normally. Otic expression of pax5 requires pax2a and fgf3, mutations in which cause vestibular defects, albeit by distinct mechanisms. Thus, pax5 works in conjunction with fgf3 and pax2a to establish and/or maintain the utricular macula and is essential for vestibular function. (c) 2006 Wiley-Liss, Inc.

PMID: 17013878 [PubMed - indexed for MEDLINE]


99. Development. 2006 Oct;133(19):3837-46.

Ephrin A/EphA controls the rostral turning polarity of a lateral commissural tract in chick hindbrain.

Zhu Y, Guthrie S, Murakami F.

SORST, Japan Science and Technology, Japan. yan.zhu@fbs.osaka-u.ac.jp

Most post-crossing commissural axons turn into longitudinal paths to make synaptic connections with their targets. Mechanisms that control their rostrocaudal turning polarity are still poorly understood. We used the hindbrain as a model system to investigate the rostral turning of a laterally located commissural tract, identified as the caudal group of contralateral cerebellar-projecting second-order vestibular neurons (cC-VC). We found that the caudal hindbrain possessed a graded non-permissive/repulsive activity for growing cC-VC axons. This non-permissiveness/repulsion was in part mediated by glycosyl-phosphatidylinositol (GPI)-anchored ephrin A. We further demonstrated that ephrin A2 was distributed in a caudal-high/rostral-low gradient in the caudolateral hindbrain and cC-VC axons expressed EphA receptors. Finally, perturbing ephrin A/EphA signalling both in vitro and in vivo led to rostrocaudal pathfinding errors of post-crossing cC-VC axons. These results suggest that ephrin A/EphA interactions play a key role in regulating the polarity of post-crossing cC-VC axons as they turn into the longitudinal axis.

PMID: 16968816 [PubMed - indexed for MEDLINE]


100. J Med Genet. 2007 Feb;44(2):153-60. Epub 2006 Sep 8.

Development of a genotyping microarray for Usher syndrome.

Cremers FP, Kimberling WJ, Külm M, de Brouwer AP, van Wijk E, te Brinke H, Cremers CW, Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley PM, Haralambous E, Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy BP, Silvestri G, McKay GJ, Koenekoop RK, Millan JM, Rosenberg T, Joensuu T, Sankila EM, Weil D, Weston MD, Wissinger B, Kremer H.

Department of Human Genetics, and Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. F.Cremers@antrg.umcn.nl

BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. RESULTS: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. CONCLUSION: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

PMCID: PMC2598068 PMID: 16963483 [PubMed - indexed for MEDLINE]