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Bernd Fritzsch - One of the best experts on this subject based on the ideXlab platform.

  • Inner ear development: building a spiral ganglion and an organ of Corti out of unspecified ectoderm
    Cell and Tissue Research, 2015
    Co-Authors: Bernd Fritzsch, Ning Pan, Israt Jahan, Karen L. Elliott
    Abstract:

    The mammalian inner ear develops from a placodal thickening into a complex labyrinth of Ducts with five sensory organs specialized to detect position and movement in space. The mammalian ear also develops a spiraled Cochlear Duct containing the auditory organ, the organ of Corti (OC), specialized to translate sound into hearing. Development of the OC from a uniform sheet of ectoderm requires unparalleled precision in the topological developmental engineering of four different general cell types, namely sensory neurons, hair cells, supporting cells, and general otic epithelium, into a mosaic of ten distinctly recognizable cell types in and around the OC, each with a unique distribution. Moreover, the OC receives unique innervation by ear-derived spiral ganglion afferents and brainstem-derived motor neurons as efferents and requires neural-crest-derived Schwann cells to form myelin and neural-crest-derived cells to induce the stria vascularis. This transformation of a sheet of cells into a complicated interdigitating set of cells necessitates the orchestrated expression of multiple transcription factors that enable the cellular transformation from ectoderm into neurosensory cells forming the spiral ganglion neurons (SGNs), while simultaneously transforming the flat epithelium into a tube, the Cochlear Duct, housing the OC. In addition to the cellular and conformational changes forming the Cochlear Duct with the OC, changes in the surrounding periotic mesenchyme form passageways for sound to stimulate the OC. We review molecular developmental data, generated predominantly in mice, in order to integrate the well-described expression changes of transcription factors and their actions, as revealed in mutants, in the formation of SGNs and OC in the correct position and orientation with suitable innervation. Understanding the molecular basis of these developmental changes leading to the formation of the mammalian OC and highlighting the gaps in our knowledge might guide in vivo attempts to regenerate this most complicated cellular mosaic of the mammalian body for the reconstitution of hearing in a rapidly growing population of aging people suffering from hearing loss.

  • Conditional Sox10 mutants reveal differential migration of spiral ganglion neurons.
    2014
    Co-Authors: Yanyan Mao, Simone Reiprich, Michael Wegner, Bernd Fritzsch
    Abstract:

    p75NTR in situ hybridization labels all sensory neurons of the ear and the inner pillar cells of the organ of Corti [40]. Labeling both cell types with a single marker allows for measuring the distance between the spiral ganglion neurons (SPG) and the inner pillar cells (IPC) (lilac bar in A’, B’, A”, B”). Note the altered ganglion cell distribution (A, B) and the 4 times increase in distance between the SPG and the Cochlear Duct (green bar), but constant distance to the inner pillar cells (red bar) in these littermates. Abbreviations: BT, basal tip; VG, vestibular ganglion; U, utricle; SPG, spiral ganglion neurons; IPC, inner pillar cells. Bar indicates 100 um.

  • Foxg1Cre∶Gata3f/f mice show loss of Cochlear neurosensory epithelia.
    2013
    Co-Authors: Jeremy S. Duncan, Bernd Fritzsch
    Abstract:

    A) E16.5 Control ear showing lipophilic dye tracing of normal wild-type distribution of efferent, VII, and GP nerves. A portion of the posterior projection of the VII nerve was removed in order to visualize the Cochlear (C) afferents. Injection of dye was in ipsilateral rhombomere 4. B,C) Injection of lipophilic dye in E16.5 Foxg1Cre:Gata3f/f hindbrain to label fibers to the ear as in (A), except in addition red lipophilic dye was injected to label the Cochlear and vestibular afferents. The facial nerve (VII) shows a normal course around the ear. No fibers are projecting towards the Cochlear Duct (c). Blue arrow indicates fibers projecting to a non-existent horizontal canal. White arrow indicates fibers initially projecting to the location of where a posterior canal should reside, but in its absence these fibers diverge and project to the remaining epithelia. D) Foxg1Cre: Gata3f/f ear labeled with Myo7a immunohistochemistry shown in red. Positive cells are located in the saccule, utricle, and one canal crista. There are no Myo7a positive cells in the Cochlear Duct. In the center of the single canal crista there is a lack of non-sensory epithelia (blue arrow). D′′) Low magnification of entire mutant ear. E) SEM of E16.5 control organ of Corti, showing the normal stereotyped pattern of four rows of hair cells (lilac). The early tectorial membrane could be visualized during preparation. F) SEM showing a flat epithelium in the Foxg1Cre: Gata3f/f ear. No hair cells could be identified in the Cochlear Duct. No tectorial membrane was observed during dissection. There was also a lack of microvilli on the remaining epithelia. G,H) Inner ear efferents and FBM were both labeled with red dye on the same side simultaneously where the facial nerve wraps around the ear. The contralateral FBM were labeled with green dye. G) Efferent cell bodies can be seen (as marked by the white oval). These cells were labeled from the contralateral ear. H) Efferent axons can be seen (arrow) as they diverge from the facial nerve. All aspects of efferent cell body location are in concordance with wild type phenotype. I and J) Showing Atoh1 in situ hybridization (ISH) at E14.5. Insets show positive expression remains in the vestibular portion of the ear correlating with the presence of Myo7a positive cells, and absence within the mutant Cochlear Duct. K and L) Showing Sox2 ISH at e12.5. Sox2 is necessary for specification of sensory epithelia in the ear. In the control ear (K) all sensory epithelia show positive expression. In the Foxg1Cre: Gata3f/f ear (L) the vestibular portion is positive for Sox2 expression while the organ of Corti shows no expression. M and N) Showing Jag1 ISH at E14.5. Jag1 is a known marker of the prosensory domain and necessary for sensory cell development in the inner ear. Jag1 expression appears more highly upregulated with respect to topology and intensity in the mutant (N) compared to control (M). Anterior is to the right and dorsal is up in all images. Scale bars C and D indicate 10 µm; G,H, K-N indicate 100 µm, I and J indicate 200 µm. A-F, dorsal is up and anterior is to the right. G,H rostral is to the right. c, cochlea; p, posterior crista; hc, horizontal crista; ac, anterior crista; VII, facial nerve; gp, greater petrosal nerve; u, uturicle; s, saccule; FBM, facial branchial motorneurons; IN, intermediate nerve; oc, organ of Corti.

  • Pax2-Cre: Gata3f/f ears have altered neurosensory development.
    2013
    Co-Authors: Jeremy S. Duncan, Bernd Fritzsch
    Abstract:

    A and B) 3D reconstruction of a Pax2-Cre: Gata3f/f ear compared to control at P0. Colors correspond to figure 2. A) P0 control ear yellow and blue correspond to scala tympani and scala vestibule which are absent in the mutant (B). Only the base of the endolymphatic Duct has been recsonstructed in both images. C,D,F,G) E18.5 Gata3 LacZ expression in Gata3 heterozygotes with a wildtype allele (C,D) and with a conditional deletion of the second floxed allele with Pax2-Cre (F,G). In the mutant there is a reDuction in the length of the cochlea. The mutant spiral ganglion (SG) is not adjacent to the Cochlear Duct, rather all spiral ganglion cells are coalesced in a single area. E,H-K) Lipophilic dye tracing as in Fig. 3. In contrast to the Foxg1Cre mutant spiral ganglion cells are present and project to the cochlea. In contrast to control, (E), innervation to the cochlea is patchy and is targeted to specific areas. Afferent radial fibers project a straight and short distance in the control in contrast to the mutant where the radial fibers project a long distance from a single location of the spiral ganglion neurons to the patches of sensory epithelia. I-K) Show higher magnification of innervation to sensory epithelia. L) Immunohistochemistry for α-tubulin (green) and Myo7a (red) of mutant Cochlear Duct. Tubulin staining also shows patchy innervation to the Cochlear Duct. The remaining innervation targets patches of hair cells that remain along the length of the Cochlear Duct. Scale bars represent 100 µm. c, cochlea; pc, posterior crista; hc, horizontal crista; ac, anterior crista; VII, facial nerve; gg, geniculate ganglion; u, uturicle; s, saccule; sg, spiral ganglion; oc, organ of Corti.

  • Morphological development of Foxg1Cre∶ Gata3f/f ears.
    2013
    Co-Authors: Jeremy S. Duncan, Bernd Fritzsch
    Abstract:

    3D reconstruction of Foxg1Cre:Gata3f/f inner ears compared to control; utilizing confocal microscopy and Amira software. A-C) At E9.5 there is very little difference in size between the two genotypes. By E10.5 there is a slight reDuction in the mutant ear dorsally. At E16.5 there is morphologic development of a Cochlear Duct (red) in the mutant ear, although it is truncated compared to control. There is also morphologic development of the vestibular portion of the mutant ear (green) although it is highly abnormal. While there is a noticeable saccular out-pouching, none of the other vestibular structures are easily identifiable. The endolymphatic Duct is present in the mutant ear (purple) and extends dorsally. Dorsal is up anterior is to the right in all images. All scale bars represent 100 µm.

Akinobu Kakigi - One of the best experts on this subject based on the ideXlab platform.

  • effect of artificial endolymph injection into the Cochlear Duct on perilymph potassium
    Operations Research Letters, 2009
    Co-Authors: Akinobu Kakigi, Alec N Salt, Taizo Takeda
    Abstract:

    Objective: To investigate the relationship between endolymphatic hydrops and perilymphatic potassium. Methods: 20 pigmented guinea pigs were used: 10 for scala vestibuli study and 10 for scala tympani study. Acute endolymphatic hydrops was produced by microinjection of an artificial endolymph into the scala media. Injections were performed in the second turn at rates up to 500 nl/min for a period of 10 min. The injection volume was up to 5 µl. EndoCochlear potential (EP) was monitored during injections. Simultaneous with the injections, the potassium concentrations in scala vestibuli (KSV) or tympani (KST) perilymph were measured with ion-sensitive double-barreled microelectrodes sealed into in the scalae in the 3rd turn with cyanoacrylate glue. Results: For endolymphatic injections of ≤3 µl, perilymphatic KSV and KST changes were generally small. With larger volume injections, substantial increases in both KST and KSV were observed, with larger increases observed in KSV compared to KST. Conclusion: An increase of perilymph potassium ion concentration is associated with endolymphatic hydrops and the perilymphatic increase could contribute to the inner ear dysfunction of patients with Meniere’s disease. Although mild hydrops may not cause perilymphatic changes, extended hydrops may increase perilymphatic K which could contribute to vertigo and/or hearing loss during the attack.

  • effect of artificial endolymph injection into the Cochlear Duct on the endoCochlear potential
    Hearing Research, 1998
    Co-Authors: Akinobu Kakigi
    Abstract:

    We investigated the effect of acute endolymphatic hydrops on the positive endoCochlear potential (+EP) and negative endoCochlear potential (-EP). The +EP was measured in guinea pigs during injection (without outlet) and perfusion (with outlet) of artificial endolymph into the Cochlear Duct. The -EP was measured during anoxia after the injection or the perfusion had finished. Injection of artificial endolymph produced a slight transient increase in the +EP, and a significant decrease in the magnitude of the -EP. Chronic endolymphatic hydrops produces both +EP and -EP decrease. The +EP decrease in chronic endolymphatic hydrops may cause the chronic change of the inner ear. The +EP increase in acute endolymphatic hydrops may be caused by a shift of the basilar membrane. However, the mechanism of the 'transient' +EP increase is not clear. The -EP decrease was not observed in animals whose Cochlear Duct was perfused with artificial endolymph. Therefore, the artificial endolymph itself did not cause the decrease in magnitude of the -EP. Dysfunction of the hair cells is a possible explanation for the -EP decrease but the mechanism of such a decrease is not clear in the present study. However, the results of this study support the notion that small increases in endolymphatic pressure below the resolution of recent measurements (DeMott and Salt, 1997) can lead directly to a reDuction of the -EP during hydrops. The animal model described here can eliminate the chronic effect of hydrops, therefore, this model is useful for investigations into the effect of hydrops itself on the inner ear and the mechanism of hearing loss in Meniere's disease.

Alain Dabdoub - One of the best experts on this subject based on the ideXlab platform.

Matthew W. Kelley - One of the best experts on this subject based on the ideXlab platform.

  • Comparative expression of Efnb2, Pou3f4, and Sox9 at E13.5 and E16.5.
    2014
    Co-Authors: Steven Raft, Matthew W. Kelley, Thomas M Coate, Bryan E. Crenshaw
    Abstract:

    Adjacent transverse sections through embryos at two developmental stages, hybridized to detect Efnb2 (A,D), Pou3f4 (B, E), or Sox9 (C, F). c, cartilaginous Cochlear capsule; cd, Cochlear Duct; eam, external auditory canal; eu, nascent eustacian tube; i, incus; m, malleus; ph, pharynx, spg, spiral ganglion, s, stapes. Asterisk highlights the facial nerve. Double arrowheads in (A–C) highlight overlapping Efnb2 and Pou3f4 signals and relatively weak Sox9 signal dorsal to the stapes. Single arrowhead in (F) highlights a lack of Sox9 signal in the corresponding region at E16.5. White arrowheads in (D, E) highlight overlapping Efnb2 and Pou3f4 signals at the forming S–V joint. Scale bar represents 200 microns in (A–C) and 250 microns in (D–F).

  • making connections in the inner ear recent insights into the development of spiral ganglion neurons and their connectivity with sensory hair cells
    Seminars in Cell & Developmental Biology, 2013
    Co-Authors: Thomas M Coate, Matthew W. Kelley
    Abstract:

    In mammals, auditory information is processed by the hair cells (HCs) located in the cochlea and then rapidly transmitted to the CNS via a specialized cluster of bipolar afferent connections known as the spiral ganglion neurons (SGNs). Although many anatomical aspects of SGNs are well described, the molecular and cellular mechanisms underlying their genesis, how they are precisely arranged along the Cochlear Duct, and the guidance mechanisms that promote the innervation of their hair cell targets are only now being understood. Building upon foundational studies of neurogenesis and neurotrophins, we review here new concepts and technologies that are helping to enrich our understanding of the development of the nervous system within the inner ear.

  • Scx expression in the developing mouse Cochlear Duct.
    2013
    Co-Authors: Zoe F. Mann, Weise Chang, Kyu Yup Lee, Kelly A. King, Matthew W. Kelley
    Abstract:

    (A,B) Images show maximal confocal z-projections through E13.5 Cochlear sections showing broad expression of Scx-GFP throughout the Cochlear epithelium (green). Note the gradient in expression levels, in particular in the roof of the Duct, between base and apex. The prosensory region (PS), flanked by the developing greater and lesser epithelial ridges (GER and LER), is marked based on expression of SOX2 (red). Auditory glia within the spiral ganglion (SG) is also present for Sox2. (C, D) Maximal z-projections taken through the Cochlear Duct at E15. Scx-GFP expression is present in fibrocytes and the developing otic capsule, most of the Cochlear Duct, spiral ganglion neurons, and the future spiral limbus. Expression still appears to be more intense in the base, consistent with a base-to-apex gradient of expression (E,F) Maximal z-projections through the Cochlear Duct at P0. Scx-GFP expression is restricted to the outer sulcus (OS), developing interdental cells (white arrows), medial region of the inner sulcus (IS), spiral limbus (SL), stria vascularis and the inner hair cells (IHCs). Occasional pillar cells also express Scx and weak expression was observed in Reissner’s membrane. The pattern of Scx expression is similar in both the basal and apical regions, indicating that the base-to-apex gradient in Scx expression is no longer present. Scale bar is 100 µm

  • Scx is expressed in both mesenchymal and epithelial cells within the inner ear.
    2013
    Co-Authors: Zoe F. Mann, Weise Chang, Kyu Yup Lee, Kelly A. King, Matthew W. Kelley
    Abstract:

    Images show maximal confocal z-projections through cross-sections of the inner ear from Scx-GFP mice at E13.5 (A) and E15.5 (B). At E13.5 Scx is expressed in the developing otic capsule, in otic fibrocytes (white arrow heads) and throughout the basal turn of the Cochlear Duct. Expression of Scx in the middle and apical Cochlear turns is noticeably lower. By E15.5 Scx expression is notable in the developing spiral limbus (SL) of the basal turn as well as in all four turns of the Cochlear Duct. While broad expression persists in the basal turn, expression in the remaining turns is more restricted with the most intense expression localized to the lateral floor and ceiling of the Duct. Scx expression is also still evident in otic fibrocytes (arrowheads). Scale bar is 100 µm.

  • myosin ii regulates extension growth and patterning in the mammalian Cochlear Duct
    Development, 2009
    Co-Authors: Norio Yamamoto, Takayuki Okano, Robert S Adelstein, Matthew W. Kelley
    Abstract:

    The sensory epithelium of the mammalian cochlea comprises mechanosensory hair cells that are arranged into four ordered rows extending along the length of the Cochlear spiral. The factors that regulate the alignment of these rows are unknown. Results presented here demonstrate that cellular patterning within the cochlea, including the formation of ordered rows of hair cells, arises through morphological remodeling that is consistent with the mediolateral component of convergent extension. Non-muscle myosin II is shown to be expressed in a pattern that is consistent with an active role in cellular remodeling within the cochlea, and genetic or pharmacological inhibition of myosin II results in defects in cellular patterning that are consistent with a disruption in convergence and extension. These results identify the first molecule, myosin II, which directly regulates cellular patterning and alignment within the Cochlear sensory epithelium. Our results also provide insights into the cellular mechanisms that are required for the formation of highly ordered cellular patterns.

Vincent Y W Lin - One of the best experts on this subject based on the ideXlab platform.

  • the effect of Cochlear size on Cochlear implantation outcomes
    BioMed Research International, 2019
    Co-Authors: Jafri Kuthubutheen, Amandeep Grewal, Sean P Symons, J M Nedzelski, David Shipp, Vincent Y W Lin
    Abstract:

    Objectives. To determine if Cochlear Duct length and Cochlear basal diameter, measured using routinely available radiology software, affect hearing outcomes after Cochlear implantation with two different length electrodes. Methods. 55 patients who received a Med-El Flex electrode were retrospectively reviewed. 34 patients received the Flex 31 electrode (31mm) and 21 patients received the Flex 28 electrode (28mm). Preoperative high-resolution CT scans of the temporal bone were reformatted in the axial and coronal plane. The basal diameter of the Cochlear (A-value) and the outer-wall lengths of the Cochlear Duct were measured using readily available imaging software. Postoperative plane X-rays were used to determine the degree of electrode insertion and the number of electrodes within the cochlea and speech discrimination scores at 6 months were evaluated. Results. The Cochlear metrics obtained were comparable with those previously published in the literature. There was no significant difference in the degree of insertion or speech outcomes between the two electrode lengths. However, when the group who had received the shorter electrode were analysed, there was an association seen between both Cochlear Duct length and Cochlear diameter and speech outcomes. Conclusions. Cochlear size may be a factor in determining speech outcomes that cannot be explained solely by insertion depth or degrees of insertion. Further studies are required to determine if Cochlear Duct length is an independent predictor of speech outcomes.

  • comprehensive expression of wnt signaling pathway genes during development and maturation of the mouse cochlea
    PLOS ONE, 2016
    Co-Authors: Ruishuang Geng, Vincent Y W Lin, Teppei Noda, Joanna F Mulvaney, Albert S B Edge, Alain Dabdoub
    Abstract:

    Background In the inner ear Wnt signaling is necessary for proliferation, cell fate determination, growth of the Cochlear Duct, polarized orientation of stereociliary bundles, differentiation of the periotic mesenchyme, and homeostasis of the stria vascularis. In neonatal tissue Wnt signaling can drive proliferation of cells in the sensory region, suggesting that Wnt signaling could be used to regenerate the sensory epithelium in the damaged adult inner ear. Manipulation of Wnt signaling for regeneration will require an understanding of the dynamics of Wnt pathway gene expression in the ear. We present a comprehensive screen for 84 Wnt signaling related genes across four developmental and postnatal time points.