A5005813264- Hearing, Cochlea, Tinnitus, Genetics
- Marine animal studies overview
- Zebrafish Biomedical Research Applications
- Cellular transport and secretion
- Connexins and lens biology
- Congenital heart defects research
- Vestibular and auditory disorders
- Neurobiology and Insect Physiology Research
- Erythrocyte Function and Pathophysiology
- Ion Channels and Receptors
- Biochemical Analysis and Sensing Techniques
- Retinal Development and Disorders
- Lipid Membrane Structure and Behavior
- Cancer-related molecular mechanisms research
- Endoplasmic Reticulum Stress and Disease
- Fungal and yeast genetics research
- Developmental Biology and Gene Regulation
- Physiological and biochemical adaptations
- RNA and protein synthesis mechanisms
- Underwater Vehicles and Communication Systems
- RNA regulation and disease
- Single-cell and spatial transcriptomics
- Ion channel regulation and function
- Axon Guidance and Neuronal Signaling
- Extracellular vesicles in disease
Stanford University
2020-2024
Stanford Medicine
2019-2023
Vollum Institute
2010-2020
Oregon Health & Science University
2011-2020
Howard Hughes Medical Institute
2008-2012
Max Planck Institute for Developmental Biology
1998-2007
Max Planck Institute for Medical Research
2003
European Synchrotron Radiation Facility
2003
Max Planck Society
1998-2000
University of California, Los Angeles
1994-1995
Hair cells detect sound and movement transmit this information via specialized ribbon synapses. Here we report that asteroid , a gene identified in an ethylnitrosourea mutagenesis screen of zebrafish larvae for auditory/vestibular mutants, encodes vesicular glutamate transporter 3 (Vglut3). A splice site mutation exon 2 vglut3 results severe truncation the predicted protein product morpholinos directed against ATG start or affected junction replicate phenotype. In situ hybridization shows is...
The senses of hearing and balance in vertebrates rely on the sensory hair cells (HCs) inner ear. central element HC's transduction apparatus is a mechanically gated ion channel unknown identity. Here we report that zebrafish ortholog Drosophila no mechanoreceptor potential C (nompC), which encodes transient receptor (TRP) channel, critical for HC mechanotransduction. In larvae, nompC selectively expressed HCs. Morpholino-mediated removal function eliminated transduction-dependent endocytosis...
The stone-like otoliths from the ears of teleost fishes are involved in balance and hearing consist calcium carbonate crystallites embedded a protein framework. We report that previously unknown gene, starmaker , is required zebrafish for otolith morphogenesis. Reduction activity by injection modified antisense oligonucleotides causes change crystal lattice structure thus morphology. expression pattern along with presence on growing otolith, suggest levels control shape otoliths.
The molecular basis of sensory hair cell mechanotransduction is largely unknown. In order to identify genes that are essential for mechanosensory function, we characterized a group recently isolated zebrafish motility mutants. These mutants defective in balance and swim circles but have no obvious morphological defects. We examined the using calcium imaging acoustic-vibrational tactile escape responses, high resolution microscopy neuroepithelia live larvae, recordings extracellular...
The zebrafish (Danio rerio) possesses two mechanosensory organs believed to be homologous each other: the inner ear, which is responsible for senses of audition and equilibrium, lateral line organ, involved in detection water movements. Eight circler or auditory/vestibular mutants appear have defects specific sensory hair cell function. genes may therefore encode components mechanotransduction apparatus and/or orthologous counterparts underlying human hereditary deafness. In this report, we...
Significance Our understanding of the molecular basis our sense hearing and balance has improved significantly, although some key players in sensory hair cells have yet to be identified. Sensory depend on extracellular filaments known as tip links transduce mechanical stimuli into electrical signals. We demonstrate that link protein PCDH15 interacts with two integral member proteins, TMC1 TMC2, which recently been put forth candidates for mechanotransduction channel.
When a growing cell expands, lipids and proteins must be delivered to its periphery. Although this phenomenon has been observed for decades, it remains unknown how the secretory pathway responds growth signaling. We demonstrate that control of Golgi phosphatidylinositol-4-phosphate (PI(4)P) is required growth-dependent secretion. The phosphoinositide phosphatase SAC1 accumulates at in quiescent cells down-regulates anterograde trafficking by depleting PI(4)P. localization requires...
Ribbon synapses of the ear, eye and pineal gland contain a unique protein component: Ribeye. Ribeye consists novel aggregation domain spliced to transcription factor CtBP2 is one most abundant proteins in synaptic ribbon bodies. Although importance for function physical integrity has been shown, specific role synaptogenesis not described. Here, we have modulated expression zebrafish hair cells examined synapse development. Knockdown ribeye resulted fewer stimulus-evoked action potentials...
L-type calcium channels (Ca(V)1) are involved in diverse processes, such as neurotransmission, hormone secretion, muscle contraction, and gene expression. In this study, we uncover a role for Ca(V)1.3a regulating the architecture of cellular structure, ribbon synapse, developing zebrafish sensory hair cells. By combining vivo imaging with confocal super-resolution structured illumination microscopy, found that genetic disruption or acute block led to enlargement synaptic ribbons Conversely,...
Neuromodulin (also designated P-57, GAP-43, B-50) is a major presynaptic substrate for protein kinase C. Phosphorylation of neuromodulin decreases its affinity calmodulin, suggesting that may function to bind and concentrate calmodulin at specific sites within neurons, releasing locally in response phosphorylation by C (Alexander, K. A., Cimler, B. M., Meier, E., Storm, D. R. (1987) J. Biol. Chem. 262, 6108-6113). In the present study, we have constructed characterized several mutant...
Vertebrate mechanosensory hair cells contain a narrow "pericuticular" zone which is densely populated with small vesicles between the cuticular plate and cellular junctions near apical surface. The presence of many cytoplasmic suggests that surface has high turnover rate. significance intense membrane trafficking at not known. Using marker endocytosis, styryl dye FM1-43, this report shows rapid endocytosis in zebrafish lateral line sensory calcium calmodulin dependent partially blocked by...
In the sensory receptors of both eye and ear, specialized apical structures have evolved to detect environmental stimuli such as light sound. Despite morphological divergence these differing transduction mechanisms, appear rely in part on a shared group genes for function. For example, mutations Usher (USH) cause syndrome visual acoustic-vestibular deficits humans. Several affected been identified, including USH1F gene, which encodes protocadherin 15 (PCDH15). Pcdh15 mutant mice also...
Abstract Background Vestibular reflexes coordinate movements or sensory input with changes in body head position. Vestibular-evoked responses that involve the extraocular muscles include vestibulo-ocular reflex (VOR), a compensatory eye movement to stabilize retinal images. Although an angular VOR attributable semicircular canal stimulation was reported be absent free-swimming zebrafish larvae, recent studies reveal vestibular-induced can evoked larvae by both static tilts and dynamic...
Forward genetic screens in zebrafish have identified >9000 mutants, many of which are potential disease models. Most mutants remain molecularly uncharacterized because the high cost, time and labor investment required for positional cloning. These costs limit benefit previous discourage future screens. Drastic improvements DNA sequencing technology could dramatically improve efficiency cloning other model organisms, but best strategy by has yet to be established. Using four inner ear we...
Transmembrane O-methyltransferase (TOMT/LRTOMT) is responsible for non-syndromic deafness DFNB63. However, the specific defects that lead to hearing loss have not been described. Using a zebrafish model of DFNB63, we show auditory and vestibular phenotypes are due lack mechanotransduction (MET) in Tomt-deficient hair cells. GFP-tagged Tomt enriched Golgi cells, suggesting might regulate trafficking other MET components bundle. We found Tmc1/2 proteins specifically excluded from bundle tomt...
Mutations in transmembrane inner ear (TMIE) cause deafness humans; previous studies suggest involvement the mechano-electrical transduction (MET) complex sensory hair cells, but TMIE’s precise role is unclear. In tmie zebrafish mutants, we observed that GFP-tagged Tmc1 and Tmc2b, which are subunits of MET channel, fail to target bundle. contrast, overexpression Tmie strongly enhances targeting Tmc1-GFP Tmc2b-GFP stereocilia. To identify motifs underlying regulation Tmcs, systematically...
L-type Ca2+ channels (LTCCs) drive the bulk of voltage-gated entry in vertebrate inner ear hair cells (HCs) and are essential for mammalian auditory processing. LTCC currents have been implicated neurotransmitter release at HC afferent active zone, ribbon synapse. It is likely that LTCCs play a direct role vesicle fusion; however, subcellular localization HCs has not fully resolved. Via positional cloning, we show mutations zebrafish encoding gene, cav1.3a, underlie auditory-vestibular...