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B Fritzsch

Publications and source records attributed to B Fritzsch.

At least 19 recordsLinked to original sources
PubMed2001

Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice.

Mutations at the waltzer (v) locus result in deafness and vestibular dysfunction due to degeneration of the neuroepithelium within the inner ear. Here, we use a positional cloning approach to show that waltzer encodes a novel cadherin (Cdh23), which is most closely related to the Drosophila Fat protein. A single nucleotide deletion in the v(J) allele and a single nucleotide insertion in the v allele are predicted to truncate each protein near the N-terminus and produce a functional null allele. In situ hybridization analysis showed that Cdh23 is expressed in the sensory hair cells of the inner ear, where it has been suggested to be a molecule critical for crosslinking of the stereocilia. In addition, Cdh23 is expressed in the urticulo-saccular foramen,the ductus reuniens, and Reissner's membrane, suggesting that Cdh23 may also be involved in maintaining the ionic composition of the endolymph. Finally, mutations in human CDH23 have recently been described for two loci, DFNB12 and USH1D, which cause nonsyndromic deafness, identifying waltzer as a mouse model for human hearing loss.

Alleles↗
PubMed2001

Intracranial distribution of the sympathetic system in mice: DiI tracing and immunocytochemical labeling.

The intracranial distribution of the cephalic branches of the superior cervical ganglion (scg) was studied in mice using indocarbocyanine dye (DiI) anterograde tracing. Two main branches were traced from the scg. The first branch joined the nerve of the pterygoid canal (the vidian nerve), npc, from which several intracranial sympathetic branches passed to the branches of the trigeminal nerve (tgn), abducent nerve (abn), trochlear nerve (trn), and oculomotor nerve (ocn). Most of the second branch joined the abn, from which sympathetic fibers dispersed in the distal region of the trigeminal ganglion (tgg) to form a plexus close to the ganglion's branches. Branches from this plexus joined the branches of the tgn, trn, and ocn. Several minor branches arising from the second branch of the scg were also observed. One formed a sympathetic plexus around the internal carotid artery (ica); a second formed a sympathetic plexus in the proximal region of tgg, close to its root; and a third branch coursed laterally to reach the ear by passing along the greater petrosal nerve (gpn). All of the intracranial trajectories traced from scg were found to be catecholaminergic, and likely sympathetic, using tyrosine hydroxylase (TH) immunocytochemistry.

Abducens Nerve↗
PubMed2001

Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear.

Patterning the vertebrate ear requires the coordinated expression of genes that are involved in morphogenesis, neurogenesis, and hair cell formation. The zinc finger gene GATA-3 is expressed both in the inner ear and in afferent and efferent auditory neurons. Specifically, GATA-3 is expressed in a population of neurons in rhombomere 4 that extend their axons across the floor plate of rhombomere 4 (r4) at embryonic day 10 (E10) and reach the sensory epithelia of the ear by E13.5. The distribution of their cell bodies corresponds to that of the cell bodies of the cochlear and vestibular efferent neurons as revealed by labeling with tracers. Both GATA-3 heterozygous and GATA-3 null mutant mice show unusual axonal projections, such as misrouted crossing fibers and fibers in the facial nerve, that are absent in wild-type littermates. This suggests that GATA-3 is involved in the pathfinding of efferent neuron axons that navigate to the ear. In the ear, GATA-3 is expressed inside the otocyst and the surrounding periotic mesenchyme. The latter expression is in areas of branching of the developing ear leading to the formation of semicircular canals. Ears of GATA-3 null mutants remain cystic, with a single extension of the endolymphatic duct and no formation of semicircular canals or saccular and utricular recesses. Thus, both the distribution of GATA-3 and the effects of null mutations on the ear suggest involvement of GATA-3 in morphogenesis of the ear. This study shows for the first time that a zinc finger factor is involved in axonal navigation of the inner ear efferent neurons and, simultaneously, in the morphogenesis of the inner ear.

Animals↗
PubMed2001

Proprioceptor pathway development is dependent on Math1.

The proprioceptive system provides continuous positional information on the limbs and body to the thalamus, cortex, pontine nucleus, and cerebellum. We showed previously that the basic helix-loop-helix transcription factor Math1 is essential for the development of certain components of the proprioceptive pathway, including inner-ear hair cells, cerebellar granule neurons, and the pontine nuclei. Here, we demonstrate that Math1 null embryos lack the D1 interneurons and that these interneurons give rise to a subset of proprioceptor interneurons and the spinocerebellar and cuneocerebellar tracts. We also identify three downstream genes of Math1 (Lh2A, Lh2B, and Barhl1) and establish that Math1 governs the development of multiple components of the proprioceptive pathway.

Animals↗
PubMed2001

NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development.

A key factor in the genetically programmed development of the nervous system is the death of massive numbers of neurons. Therefore, genetic mechanisms governing cell survival are of fundamental importance to developmental neuroscience. We report that inner ear sensory neurons are dependent on a basic helix-loop-helix transcription factor called NeuroD for survival during differentiation. Mice lacking NeuroD protein exhibit no auditory evoked potentials, reflecting a profound deafness. DiI fiber staining, immunostaining and cell death assays reveal that the deafness is due to the failure of inner ear sensory neuron survival during development. The affected inner ear sensory neurons fail to express neurotrophin receptors, TrkB and TrkC, suggesting that the ability of NeuroD to support neuronal survival may be directly mediated through regulation of responsiveness to the neurotrophins.

Animals↗
PubMed2000

Developmental evolutionary biology of the vertebrate ear: conserving mechanoelectric transduction and developmental pathways in diverging morphologies.

This brief overview shows that a start has been made to molecularly dissect vertebrate ear development and its evolutionary conservation to the development of the insect hearing organ. However, neither the patterning process of the ear nor the patterning process of insect sensory organs is sufficiently known at the moment to provide more than a first glimpse. Moreover, hardly anything is known about otocyst development of the cephalopod molluscs, another triploblast lineage that evolved complex 'ears'. We hope that the apparent conserved functional and cellular components present in the ciliated sensory neurons/hair cells will also be found in the genes required for vertebrate ear and insect sensory organ morphogenesis (Fig. 3). Likewise, we expect that homologous pre-patterning genes will soon be identified for the non-sensory cell development, which is more than a blocking of neuronal development through the Delta/Notch signaling system. Generation of the apparently unique ear could thus represent a multiplication of non-sensory cells by asymmetric and symmetric divisions as well as modification of existing patterning process by implementing novel developmental modules. In the final analysis, the vertebrate ear may come about by increasing the level of gene interactions in an already existing and highly conserved interactive cascade of bHLH genes. Since this was apparently achieved in all three lineages of triploblasts independently (Fig. 3), we now need to understand how much of the morphogenetic cascades are equally conserved across phyla to generate complex ears. The existing mutations in humans and mice may be able to point the direction of future research to understand the development of specific cell types and morphologies in the formation of complex arthropod, cephalopod, and vertebrate 'ears'.

Animals↗
PubMed2000

Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2.

Mutations in the human KCNQ4 gene were recently found by Kubisch et al. [Cell 96 (1999) 437-446] to cause a non-syndromic, autosomal dominant, progressive hearing loss, DFNA2. The mouse Kcnq4 orthologue was previously localized to the outer hair cells (OHCs) of the inner ear, suggesting the pathophysiological effects were due to dysfunctional OHCs. Yet, OHC dysfunction does not provide a plausible explanation for the progressive nature of the frequency specific hearing loss. We have re-examined and extended the expression analyses of KCNQ4 in the murine inner ear using RT-PCR and whole mount in situ hybridization. Our results confirmed that the rat KCNQ4 orthologue is expressed in both inner and outer hair cells. Reciprocal longitudinal gradients were found in inner hair cells (IHCs) and OHCs. The strongest expression of KCNQ4 in IHCc was in the base of the cochlea and in the apex for OHCs. Similar to the IHCs, a basal to apical gradient was present in the spiral sensory neurons. IHCs mediate hearing via their afferent sensory neurons, whereas OHCs function as active cochlear amplifiers. The complete absence of OHCs leads only to severe sensitivity reduction, but not complete hearing loss. Our data suggest that the primary defect leading to initial high frequency loss and subsequent progressive hearing loss for all frequencies may be due to spiral ganglion and/or IHC dysfunction, rather than an OHC aberration.

Animals↗
PubMed2000

FGF/FGFR-2(IIIb) signaling is essential for inner ear morphogenesis.

Interactions between FGF10 and the IIIb isoform of FGFR-2 appear to be crucial for the induction and growth of several organs, particularly those that involve budding morphogenesis. We determined their expression patterns in the inner ear and analyzed the inner ear phenotype of mice specifically deleted for the IIIb isoform of FGFR-2. FGF10 and FGFR-2(IIIb) mRNAs showed distinct, largely nonoverlapping expression patterns in the undifferentiated otic epithelium. Subsequently, FGF10 mRNA became confined to the presumptive cochlear and vestibular sensory epithelia and to the neuronal precursors and neurons. FGFR-2(IIIb) mRNA was expressed in the nonsensory epithelium of the otocyst that gives rise to structures such as the endolymphatic and semicircular ducts. These data suggest that in contrast to mesenchymal-epithelial-based FGF10 signaling demonstrated for other organs, the inner ear seems to depend on paracrine signals that operate within the epithelium. Expression of FGF10 mRNA partly overlapped with FGF3 mRNA in the sensory regions, suggesting that they may form parallel signaling pathways within the otic epithelium. In addition, hindbrain-derived FGF3 might regulate otocyst morphogenesis through FGFR-2(IIIb). Targeted deletion of FGFR-2(IIIb) resulted in severe dysgenesis of the cochleovestibular membraneous labyrinth, caused by a failure in morphogenesis at the otocyst stage. In addition to the nonsensory epithelium, sensory patches and the cochleovestibular ganglion remained at a rudimentary stage. Our findings provide genetic evidence that signaling by FGFR-2(IIIb) is critical for the morphological development of the inner ear.

Animals↗
PubMed2000

EphB2 guides axons at the midline and is necessary for normal vestibular function.

Mice lacking the EphB2 receptor tyrosine kinase display a cell-autonomous, strain-specific circling behavior that is associated with vestibular phenotypes. In mutant embryos, the contralateral inner ear efferent growth cones exhibit inappropriate pathway selection at the midline, while in mutant adults, the endolymph-filled lumen of the semicircular canals is severely reduced. EphB2 is expressed in the endolymph-producing dark cells in the inner ear epithelium, and these cells show ultrastructural defects in the mutants. A molecular link to fluid regulation is provided by demonstrating that PDZ domain-containing proteins that bind the C termini of EphB2 and B-ephrins can also recognize the cytoplasmic tails of anion exchangers and aquaporins. This suggests EphB2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water.

Animals↗
PubMed2000

Interactions between food components and drugs. Part 8: Effect of pectins and bile acid preparations forming stable mixed micelles on transport of quinine in vitro.

Interactions between quinine and acetylated pectin, amidated pectin and pectin with blockwise arrangement of the free carboxyl groups as well as interactions between quinine and bile salt preparations forming stable mixed bicelles have been investigated. A diffusion cell with two compartments and an artificial lipid membrane and a filter-grown colon carcinoma cell line (Caco-2) have been used. Depending on structural parameters, pectin preparations diminished the rate of permeation of the drug. Above the critical micelle concentration, the bile salt preparations influence the quinine transport stronger than the pectin preparations. The strongest inhibition of the quinine permeation showed a stable mixed micelle preparation consisting of glycodeoxycholate, palmitic acid and lecithin. The Caco-2 cell line appears to be not as suitable as artificial lipid membranes to study drug transport in the presence of the bile salt preparations.

Antimalarials↗
PubMed1999

Visualization of alpha9 acetylcholine receptor expression in hair cells of transgenic mice containing a modified bacterial artificial chromosome.

The alpha9 acetylcholine receptor (alpha9 AChR) is specifically expressed in hair cells of the inner ear and is believed to be involved in synaptic transmission between efferent nerves and hair cells. Using a recently developed method, we modified a bacterial artificial chromosome containing the mouse alpha9 AChR gene with a reporter gene encoding green fluorescent protein (GFP) to generate transgenic mice. GFP expression in transgenic mice recapitulated the known temporal and spatial expression of alpha9 AChR. However, we observed previously unidentified dynamic changes in alpha9 AChR expression in cochlear and vestibular sensory epithelia during neonatal development. In the cochlea, inner hair cells persistently expressed high levels of alpha9 AChR in both the apical and middle turns, whereas both outer and inner hair cells displayed dynamic changes of alpha9 AChR expression in the basal turn. In the utricle, we observed high levels of alpha9 AChR expression in the striolar region during early neonatal development and high levels of alpha9 AChR in the extrastriolar region in adult mice. Further, simultaneous visualization of efferent innervation and alpha9 AChR expression showed that dynamic expression of alpha9 AChR in developing hair cells was independent of efferent contacts. We propose that alpha9 AChR expression in developing auditory and vestibular sensory epithelia correlates with maturation of hair cells and is hair-cell autonomous.

Animals↗
PubMed1999

Characterization of G-protein betagamma expression in inner ear.

Heterotrimeric guanine nucleotide binding proteins (G-proteins) are composed of a diverse set of alpha, beta, and gamma subunits, which couple cell surface receptors to intracellular effectors, such as adenylyl cyclase, phospholipase Cbeta, and ion channels. Both the Galpha and the Gbetagamma dimers mediate effector activity and are believed to contribute to the complexity of the signaling pathway. Molecular and immunocytochemical techniques were employed to determine diversity of Gbeta and Ggamma subunit expression in the murine inner ear. PCR-based assessment of lambdaZAP unidirectional cDNA libraries, representing the cochlea and inner ear hair cells, indicated all five known Gbeta subunits were present in the cochlea, while only a subset of Ggamma isoforms were found. New or novel G-protein beta and gamma subunits were not detected. cDNAs representing Gbeta1-4 and Ggamma2, Ggamma3, Ggamma5, Ggamma8olf subunit transcripts were isolated. In addition, cDNAs corresponding to the Gbeta5 and Ggamma11 isoforms exhibited restricted expression to inner and outer hair cells, respectively. Antisera specific for Gbeta3, Gbeta4, Ggamma3, Ggamma5 and Ggamma11 stained spiral ganglion and neurosensory hair cells. A unique finding was the variable topological distribution of Ggamma3 in the spiral ganglion cells along the cochlear axis. Collectively, our results demonstrate a complementary as well as differential distribution pattern for Gbeta and Ggamma isoforms exists in the inner ear. The co-localization of various G-protein isoforms within the same cell type suggests specific combinatorial Gbeta and Ggamma subunit associations may preferentially be formed. Thus, the detection of multiple subunits presumably reflects the extent of the functional diversity of inner ear signaling pathways and should provide specificity of G-protein mediated pathways.

Animals↗
PubMed1999

Making and breaking the innervation of the ear: neurotrophic support during ear development and its clinical implications.

Analyses of single and double mutants of members of the neurotrophin family and their receptors are reviewed. These data demonstrate that the two neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3), and their high-affinity receptors trkB and trkC, are the sole support for the developing afferent innervation of the ear. Neurotrophins are first expressed in the otocyst around the time afferent sensory neurons become postmitotic. They are crucial for the survival of certain topologically distinct populations of sensory neurons. BDNF supports all sensory neurons to the semicircular canals, most sensory neurons to the saccule and utricle, and many sensory neurons to the apex and middle turn of the cochlea. In contrast, NT-3 supports few sensory neurons to the utricle and saccule, all sensory neurons to the basal turn of the cochlea and most sensory neurons to the middle and apical turn. Some topologically restricted effects reflect the pattern of neurotrophin distribution as revealed by in situ hybridization (e.g., loss of all innervation to the semicircular canal sensory epithelia in BDNF or trkB mutants). However, other topologically restricted effects cannot be explained on the basis of current knowledge of neurotrophin or neurotrophin receptor distribution. Data on mutants also support the notion that BDNF may play a role in neonatal plastic reorganization of the pattern of innervation in the ear and possibly the brainstem. In contrast, data obtained thus far on the ability of neurotrophins to rescue adult sensory neuron after insults to cochlear hair cells are less compelling. The ear is a model system to test the interactions of the two neurotrophins, BDNF and NT-3, with their two high-affinity receptors, trkB and trkC.

Adult↗
PubMed1999

Whole-mount procedures for simultaneous visualization of nerves, neurons, cartilage and bone.

Herein are described two techniques to selectively label and/or stain afferent and efferent fibers and their cell bodies and simultaneously stain bone and cartilage. One technique uses anti-acetylated alpha-tubulin immunohistochemistry to follow the course, peripheral branching, and origin of the ventral spinal nerve innervating the axial musculature and a second uses anterograde and retrograde transport of selectively applied 3 kDa biotin dextran amines to identify specific afferent and efferent projections and their cell bodies. Both procedures can be combined with an enzyme clearing and staining procedure for the simultaneous visualization of bone (alizarin red S) and cartilage (alcian blue) in whole-mount preparations. Myelinated and unmyelinated nerve fibers are stained dark brown with the 3,3' diaminobenzidine tetrahydrochloride (DAB) reaction product, whereas cartilage is stained blue (alcian blue) and bone is red (alizarin red S). The combination of these procedures provides a simultaneous three-dimensional understanding of the topography of afferent and efferent projections and their cell bodies and the axial and appendicular skeletal system, which is key to understanding the compartmental relationships of the spinal cord with respect to the axial and appendicular skeleton.

3,3'-Diaminobenzidine↗
PubMed1999

Incomplete segregation of endorgan-specific vestibular ganglion cells in mice and rats.

The endorgan-specific distribution of vestibular ganglion cells was studied in neonatal and postnatal rats and mice using indocarbocyanine dye (DiI) and dextran amines for retrograde and anterograde labeling. Retrograde DiI tracing from the anterior vertical canal labeled neurons scattered throughout the whole superior vestibular ganglion, with denser labeling at the dorsal and central regions. Horizontal canal neurons were scattered along the dorsoventral axis with more clustering toward the dorsal and ventral poles of this axis. Utricular ganglion cells occupied predominantly the central region of the superior vestibular ganglion. This utricular population overlapped with both the anterior vertical and horizontal canals' ganglion cells. Posterior vertical canal neurons were clustered in the posterior part of the inferior vestibular ganglion. The saccular neurons were distributed in the two parts of the vestibular ganglion, the superior and inferior ganglia. Within the inferior ganglion, the saccular neurons were clustered in the anterior part. In the superior ganglion, the saccular neurons were widely scattered throughout the whole ganglion with more numerous neurons at the posterior half. Small and large neurons were labeled from all endorgans. Examination of the fiber trajectory within the superior division of the vestibular nerve showed no clear lamination of the fibers innervating the different endorgans. These results demonstrate an overlapping pattern between the different populations within the superior ganglion, while in the inferior ganglion, the posterior canal and saccular neurons show tighter clustering but incomplete segregation. This distribution implies that the ganglion cells are assigned for their target during development in a stochastic rather than topographical fashion.

Animals↗
PubMed1998

Nerve dependency of developing and mature sensory receptor cells.

Old and recent data concerning development of sensory cells and trophic interdependency of sensory neurons and sensory cells is reviewed for the ear, the lateral line system, the electroreceptive system, and the taste system. All sensory neurons originate from placodes. However, only most ear, lateral line and electrosensory cells derive from placodes, while the taste sensory cell originate locally. All sensory cells apparently are nerve independent for their formation, and at least sensory cells in the ear and the taste system share the neurotrophic support for their specific sensory neurons. Later, most of these sensory cells appear to depend, to a variable degree, on some innervation for maintenance. While the molecular nature of the signal cascade from sensory cells to sensory neurons is known in at least two systems, nothing is known about the molecular nature of the signal cascade from the sensory neurons back to the sensory cells.

Animals↗
PubMed1998

Purification and structural characterization of insulin and glucagon from the bichir Polypterus senegalis (Actinopterygii: Polypteriformes).

The Polypteriformes (bichirs and reedfish) are a family of ray-finned fishes of ancient lineage. Insulin has been isolated from an extract of the pancreas and upper gastrointestinal tract of the bichir Polypterus senegalis and its primary structure established as A-chain: Gly-Ile-Val-Glu-Gln-Cys-Cys-Asp-Thr-Pro10-Cys-Ser- Leu-Tyr-Asp-Leu-Glu-Asn-Tyr-Cys20-Asn: B-chain: Ala-Ala-Asn-Arg-His-Leu-Cys-Gly-Ser-His10-Leu-Val- Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly20-Asn-Arg-Gly-Phe- Phe-Tyr-Ile-Pro-Ser-Lys30-Met. Despite the fact that Polypterus insulin contains several unusual structural features that are not found in insulins from other jawed fish (Asp at A-8, Thr at A-9, Arg at B-4, Asn at B-21, Ile at B-27, Met at B-31), all the residues in human insulin that are involved in receptor binding, dimerization, and hexamerization have been conserved. A comparison of the structures of insulins from a range of species indicates that Polypterus insulin most closely resembles paddlefish insulin II (seven amino acid substitutions). In contrast, Polypterus glucagon (His-Ser- Gln-Gly-Thr-Phe-Thr-Asn-Asp-Tyr10-Thr-Lys-Tyr- Gln-Asp-Ser-Arg-Arg-Ala-Gln20-Asp-Phe-Val-Gln- Trp-Leu-Met-Ser-Asn) most closely resembles the glucagons from the gar Lepisosteus spatula and the bowfin Amia calva (four amino acid substitutions). The data are consistent with the conclusion based on comparison of morphological characteristics that the Polypterids are the most basal living group of the Actinopterygians with evolutionary connections to both the Acipenserids and the Neopterygians.

Amino Acid Sequence↗