Talk:Hearing - Inner Ear Development

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Cite this page: Hill, M.A. (2021, September 28) Embryology Hearing - Inner Ear Development. Retrieved from


Kolla L, Kelly MC, Mann ZF, Anaya-Rocha A, Ellis K, Lemons A, Palermo AT, So KS, Mays JC, Orvis J, Burns JC, Hertzano R, Driver EC & Kelley MW. (2020). Characterization of the development of the mouse cochlear epithelium at the single cell level. Nat Commun , 11, 2389. PMID: 32404924 DOI.

Characterization of the development of the mouse cochlear epithelium at the single cell level

Mammalian hearing requires the development of the organ of Corti, a sensory epithelium comprising unique cell types. The limited number of each of these cell types, combined with their close proximity, has prevented characterization of individual cell types and/or their developmental progression. To examine cochlear development more closely, we transcriptionally profile approximately 30,000 isolated mouse cochlear cells collected at four developmental time points. Here we report on the analysis of those cells including the identification of both known and unknown cell types. Trajectory analysis for OHCs indicates four phases of gene expression while fate mapping of progenitor cells suggests that OHCs and their surrounding supporting cells arise from a distinct (lateral) progenitor pool. Tgfβr1 is identified as being expressed in lateral progenitor cells and a Tgfβr1 antagonist inhibits OHC development. These results provide insights regarding cochlear development and demonstrate the potential value and application of this data set. PMCID: PMC7221106 DOI: 10.1038/s41467-020-16113-y

Schade-Mann T, Münkner S, Eckrich T & Engel J. (2020). Calcium signaling in interdental cells during the critical developmental period of the mouse cochlea. Hear. Res. , 389, 107913. PMID: 32120242 DOI.

Calcium signaling in interdental cells during the critical developmental period of the mouse cochlea

The tectorial membrane (TM), a complex acellular structure that covers part of the organ of Corti and excites outer hair cells, is required for normal hearing. It consists of collagen fibrils and various glycoproteins, which are synthesized in embryonic and postnatal development by different cochlear cell types including the interdental cells (IDCs). At its modiolar side, the TM is fixed to the apical surfaces of IDCs, which form the covering epithelium of the spiral limbus. We performed confocal membrane imaging and Ca2+ imaging in IDCs of the developing mouse cochlea from birth to postnatal day 18 (P18). Using the fluorescent membrane markers FM 4-64 and CellMask™ Deep Red on explanted whole-mount cochlear epithelium, we identified the morphology of IDCs at different z-levels of the spiral limbus. Ca2+ imaging of Fluo-8 AM-loaded cochlear epithelia revealed spontaneous intracellular Ca2+ transients in IDCs at P0/1, P4/5, and P18. Their relative frequency was lowest on P0/1, increased by a factor of 12.5 on P4/5 and decreased to twice the initial value on P18. At all three ages, stimulation of IDCs with the trinucleotides ATP and UTP at 1 and 10 μM elicited Ca2+ transients of varying amplitude and shape. Before the onset of hearing, IDCs responded with robust Ca2+ oscillations. At P18, after the onset of hearing, ATP stimulation either caused Ca2+ oscillations or an initial Ca2+ peak followed by a plateau while the UTP response was unchanged from that at pre-hearing stage. Parameters of spontaneous and nucleotide-evoked Ca2+ transients such as amplitude, decay time and duration were markedly reduced during cochlear development, whereas the kinetics of the Ca2+ rise did not show relevant changes. Whether low-frequency spontaneous Ca2+ transients are necessary for the formation and maintenance of the tectorial membrane e.g. by regulating gene transcription needs to be elucidated in further studies. Copyright © 2020 Elsevier B.V. All rights reserved. KEYWORDS: Ca(2+) transient; Cochlea; Interdental cell; Membrane imaging; P2Y receptor; Tectorial membrane DOI: 10.1016/j.heares.2020.107913


Jansson L, Ebeid M, Shen JW, Mokhtari TE, Quiruz LA, Ornitz DM, Huh SH & Cheng AG. (2019). β-Catenin is required for radial cell patterning and identity in the developing mouse cochlea. Proc. Natl. Acad. Sci. U.S.A. , 116, 21054-21060. PMID: 31570588 DOI.

Abstract Development of multicellular organs requires the coordination of cell differentiation and patterning. Critical for sound detection, the mammalian organ of Corti contains functional units arranged tonotopically along the cochlear turns. Each unit consists of sensory hair cells intercalated by nonsensory supporting cells, both specified and radially patterned with exquisite precision during embryonic development. However, how cell identity and radial patterning are jointly controlled is poorly understood. Here we show that β-catenin is required for specification of hair cell and supporting cell subtypes and radial patterning of the cochlea in vivo. In 2 mouse models of conditional β-catenin deletion, early specification of Myosin7-expressing hair cells and Prox1-positive supporting cells was preserved. While β-catenin-deficient cochleae expressed FGF8 and FGFR3, both of which are essential for pillar cell specification, the radial patterning of organ of Corti was disrupted, revealed by aberrant expression of cadherins and the pillar cell markers P75 and Lgr6. Moreover, β-catenin ablation caused duplication of FGF8-positive inner hair cells and reduction of outer hair cells without affecting the overall hair cell density. In contrast, in another transgenic model with suppressed transcriptional activity of β-catenin but preserved cell adhesion function, both specification and radial patterning of the organ of Corti were intact. Our study reveals specific functions of β-catenin in governing cell identity and patterning mediated through cell adhesion in the developing cochlea. KEYWORDS: Wnt signaling; cell adhesion; cochlea; development; hair cell PMID: 31570588 PMCID: PMC6800344 [Available on 2020-03-30] DOI: 10.1073/pnas.1910223116


Visualization of the Membranous Labyrinth and Nerve Fiber Pathways in Human and Animal Inner Ears Using MicroCT Imaging

Glueckert R, Johnson Chacko L, Schmidbauer D, Potrusil T, Pechriggl EJ, Hoermann R, Brenner E, Reka A, Schrott-Fischer A & Handschuh S. (2018). Visualization of the Membranous Labyrinth and Nerve Fiber Pathways in Human and Animal Inner Ears Using MicroCT Imaging. Front Neurosci , 12, 501. PMID: 30108474 DOI.

Glueckert R1,2, Johnson Chacko L1, Schmidbauer D1,3, Potrusil T1, Pechriggl EJ4, Hoermann R4, Brenner E4, Reka A1, Schrott-Fischer A1, Handschuh S5. Author information Abstract Design and implantation of bionic implants for restoring impaired hair cell function relies on accurate knowledge about the microanatomy and nerve fiber pathways of the human inner ear and its variation. Non-destructive isotropic imaging of soft tissues of the inner ear with lab-based microscopic X-ray computed tomography (microCT) offers high resolution but requires contrast enhancement using compounds with high X-ray attenuation. We evaluated different contrast enhancement techniques in mice, cat, and human temporal bones to differentially visualize the membranous labyrinth, sensory epithelia, and their innervating nerves together with the facial nerve and middle ear. Lugol's iodine potassium iodine (I2KI) gave high soft tissue contrast in ossified specimens but failed to provide unambiguous identification of smaller nerve fiber bundles inside small bony canals. Fixation or post-fixation with osmium tetroxide followed by decalcification in EDTA provided superior contrast for nerve fibers and membranous structures. We processed 50 human temporal bones and acquired microCT scans with 15 μm voxel size. Subsequently we segmented sensorineural structures and the endolymphatic compartment for 3D representations to serve for morphometric variation analysis. We tested higher resolution image acquisition down to 3.0 μm voxel size in human and 0.5 μm in mice, which provided a unique level of detail and enabled us to visualize single neurons and hair cells in the mouse inner ear, which could offer an alternative quantitative analysis of cell numbers in smaller animals. Bigger ossified human temporal bones comprising the middle ear and mastoid bone can be contrasted with I2KI and imaged in toto at 25 μm voxel size. These data are suitable for surgical planning for electrode prototype placements. A preliminary assessment of geometric changes through tissue processing resulted in 1.6% volume increase caused during decalcification by EDTA and 0.5% volume increase caused by partial dehydration to 70% ethanol, which proved to be the best mounting medium for microCT image acquisition. KEYWORDS: endolymph; inner ear implants; membranous labyrinth; microCT; microanatomy; nerve fiber tracking; non-destructive imaging; perilymph PMID: 30108474 PMCID: PMC6079228 DOI: 10.3389/fnins.2018.00501

Copyright © 2018 Glueckert, Johnson Chacko, Schmidbauer, Potrusil, Pechriggl, Hoermann, Brenner, Reka, Schrott-Fischer and Handschuh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Formation of the Periotic Space During the Early Fetal Period in Humans

Anat Rec (Hoboken). 2018 Apr;301(4):563-570. doi: 10.1002/ar.23764. Epub 2018 Jan 18.

Ishikawa A1, Ohtsuki S1, Yamada S1,2, Uwabe C2, Imai H3, Matsuda T3, Takakuwa T1.


The inner ear is a very complicated structure, composed of a bony labyrinth (otic capsule; OC), membranous labyrinth, with a space between them, named the periotic labyrinth or periotic space. We investigated how periotic tissue fluid spaces covered the membranous labyrinth three-dimensionally, leading to formation of the periotic labyrinth encapsulated in the OC during human fetal development. Digital data sets from magnetic resonance images and phase-contrast X-ray tomography images of 24 inner ear organs from 24 human fetuses from the Kyoto Collection (fetuses in trimesters 1 and 2; crown-rump length: 14.4-197 mm) were analyzed. The membranous labyrinth was morphologically differentiated in samples at the end of the embryonic period (Carnegie stage 23), and had grown linearly to more than eight times in size during the observation period. The periotic space was first detected at the 35-mm samples, around the vestibule and basal turn of the cochlea, which elongated rapidly to the tip of the cochlea and semicircular ducts, successively, and almost covered the membranous labyrinth at the 115-mm CRL stage or later. In those samples, several ossification centers were detected around the space. This article thus demonstrated that formation of the membranous labyrinth, periotic space (labyrinth), and ossification of the OC occurs successively, according to an intricate timetable. Anat Rec, 301:563-570, 2018. © 2018 Wiley Periodicals, Inc. KEYWORDS: human early fetus; membranous labyrinth; otic capsule; periotic space; three-dimensional kinetics PMID: 29293291 DOI: 10.1002/ar.23764

Developmental profiling of microRNAs in the human embryonic inner ear

PLoS One. 2018 Jan 26;13(1):e0191452. doi: 10.1371/journal.pone.0191452. eCollection 2018.

Chadly DM1, Best J1, Ran C1, Bruska M2, Woźniak W2, Kempisty B2, Schwartz M3, LaFleur B3, Kerns BJ3, Kessler JA4, Matsuoka AJ1,5,6.


Due to the extreme inaccessibility of fetal human inner ear tissue, defining of the microRNAs (miRNAs) that regulate development of the inner ear has relied on animal tissue. In the present study, we performed the first miRNA sequencing of otic precursors in human specimens. Using HTG miRNA Whole Transcriptome assays, we examined miRNA expression in the cochleovestibular ganglion (CVG), neural crest (NC), and otic vesicle (OV) from paraffin embedded (FFPE) human specimens in the Carnegie developmental stages 13-15. We found that in human embryonic tissues, there are different patterns of miRNA expression in the CVG, NC and OV. In particular, members of the miR-183 family (miR-96, miR-182, and miR-183) are differentially expressed in the CVG compared to NC and OV at Carnegie developmental stage 13. We further identified transcription factors that are differentially targeted in the CVG compared to the other tissues from stages 13-15, and we performed gene set enrichment analyses to determine differentially regulated pathways that are relevant to CVG development in humans. These findings not only provide insight into the mechanisms governing the development of the human inner ear, but also identify potential signaling pathways for promoting regeneration of the spiral ganglion and other components of the inner ear. PMID: 29373586 PMCID: PMC5786302 DOI: 10.1371/journal.pone.0191452


Autophagy in the Vertebrate Inner Ear

Front Cell Dev Biol. 2017 May 26;5:56. doi: 10.3389/fcell.2017.00056. eCollection 2017.

Magariños M1,2,3, Pulido S1,2, Aburto MR1, de Iriarte Rodríguez R1, Varela-Nieto I1,2,4.


Autophagy is a conserved catabolic process that results in the lysosomal degradation of cell components. During development, autophagy is associated with tissue and organ remodeling, and under physiological conditions it is tightly regulated as it plays a housekeeping role in removing misfolded proteins and damaged organelles. The vertebrate inner ear is a complex sensory organ responsible for the perception of sound and for balance. Cell survival, death and proliferation, as well as cell fate specification and differentiation, are processes that are strictly coordinated during the development of the inner ear in order to generate the more than a dozen specialized cell types that constitute this structure. Here, we review the existing evidence that implicates autophagy in the generation of the vertebrate inner ear. At early stages of chicken otic development, inhibiting autophagy impairs neurogenesis and causes aberrant otocyst morphogenesis. Autophagy provides energy for the clearing of dying cells and it favors neuronal differentiation. Moreover, autophagy is required for proper vestibular development in the mouse inner ear. The autophagy-related genes Becn1, Atg4g, Atg5, and Atg9, are expressed in the inner ear from late developmental stages to adulthood, and Atg4b mutants show impaired vestibular behavior associated to defects in otoconial biogenesis that are also common to Atg5 mutants. Autophagic flux appears to be age-regulated, augmenting from perinatal stages to young adulthood in mice. This up-regulation is concomitant with the functional maturation of the hearing receptor. Hence, autophagy can be considered an intracellular pathway fundamental for in vertebrate inner ear development and maturation. KEYWORDS: Atg4; Atg5; Beclin-1; LC3; cochlea; otic development; vestibular system PMID: 28603711 PMCID: PMC5445191 DOI: 10.3389/fcell.2017.00056

Role of BDNF and neurotrophic receptors in human inner ear development

Cell Tissue Res. 2017 Sep 19. doi: 10.1007/s00441-017-2686-9. [Epub ahead of print]

Johnson Chacko L1, Blumer MJF2, Pechriggl E2, Rask-Andersen H3, Dietl W1, Haim A4, Fritsch H2, Glueckert R1,5, Dudas J6, Schrott-Fischer A1.


The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors-p75NTR and Trk receptors-in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed. p75NTR immunostaining was most prominent in the nerve fibers that penetrate into the sensory epithelia of the cochlea, the urticule and the saccule as gestational age progresses. TrkB and TrkC expression intensified towards GW 12, at which point the BDNF mRNA localization was at its lowest. TrkA expression was limited to fiber subpopulations of the facial nerve at GW 10. In the adult human inner ear, we observed BDNF mRNA expression in the apical poles of the cochlear hair cells and supporting cells, while in the adult human utricle, the expression was localized in the vestibular hair cells. We demonstrate the highly specific staining patterns of BDNF mRNA and its putative receptors over a developmental period in which multiple hearing disorders are manifested. Our findings suggest that BDNF and neurotrophin receptors are important players during early human inner ear development. In particular, they seem to be important for the survival of the afferent sensory neurons. KEYWORDS: BDNF; Human; In situ hybridization; Inner ear; Neurotrophin receptors

PMID: 28924861 DOI: 10.1007/s00441-017-2686-9


Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti

Dev Biol. 2016 Jun 1;414(1):72-84. doi: 10.1016/j.ydbio.2016.03.027. Epub 2016 Apr 14.

Gu R1, Brown RM 2nd2, Hsu CW3, Cai T1, Crowder AL1, Piazza VG3, Vadakkan TJ3, Dickinson ME4, Groves AK5.


The transcription factor Sox2 is both necessary and sufficient for the generation of sensory regions of the inner ear. It regulates expression of the Notch ligand Jag1 in prosensory progenitors, which signal to neighboring cells to up-regulate Sox2 and sustain prosensory identity. However, the expression pattern of Sox2 in the early inner ear is very broad, suggesting that Sox2-expressing progenitors form a wide variety of cell types in addition to generating the sensory regions of the ear. We used Sox2-CreER mice to follow the fates of Sox2-expressing cells at different stages in ear development. We find that Sox2-expressing cells in the early otocyst give rise to large numbers of non-sensory structures throughout the inner ear, and that Sox2 only becomes a truly prosensory marker at embryonic day (E)11.5. Our fate map reveals the organ of Corti derives from a central domain on the medial side of the otocyst and shows that a significant amount of the organ of Corti derives from a Sox2-negative population in this region. Copyright © 2016 Elsevier Inc. All rights reserved. KEYWORDS: Cochlea; Inner ear; Organ of Corti; Otocyst; Sensory; Sox2 PMID 27090805

Temporal coupling between specifications of neuronal and macular fates of the inner ear

Dev Biol. 2016 Jun 1;414(1):21-33. doi: 10.1016/j.ydbio.2016.04.008. Epub 2016 Apr 13.

Deng X1, Wu DK2.


The inner ear is a complex organ comprised of various specialized sensory organs for detecting sound and head movements. The timing of specification for these sensory organs, however, is not clear. Previous fate mapping results of the inner ear indicate that vestibular and auditory ganglia and two of the vestibular sensory organs, the utricular macula (UM) and saccular macula (SM), are lineage related. Based on the medial-lateral relationship where respective auditory and vestibular neuroblasts exit from the otic epithelium and the subsequent formation of the medial SM and lateral UM in these regions, we hypothesized that specification of the two lateral structures, the vestibular ganglion and the UM are coupled and likewise for the two medial structures, the auditory ganglion and the SM. We tested this hypothesis by surgically inverting the primary axes of the otic cup in ovo and investigating the fate of the vestibular neurogenic region, which had been spotted with a lipophilic dye. Our results showed that the laterally-positioned, dye-associated, vestibular ganglion and UM were largely normal in transplanted ears, whereas both auditory ganglion and SM showed abnormalities suggesting the lateral but not the medial-derived structures were mostly specified at the time of transplantation. Both of these results are consistent with a temporal coupling between neuronal and macular fate specifications. Published by Elsevier Inc. KEYWORDS: Auditory ganglion; Fate determination; Inner ear development; Lineage; Neuronal fate; Saccular macula; Sensory fate; Transplantation; Utricular macula; Vestibular ganglion PMID 27083418


The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):E3864-73. doi: 10.1073/pnas.1501077112. Epub 2015 Jul 2.

Golden EJ1, Benito-Gonzalez A1, Doetzlhofer A2.


Proper tissue development requires strict coordination of proliferation, growth, and differentiation. Strict coordination is particularly important for the auditory sensory epithelium, where deviations from the normal spatial and temporal pattern of auditory progenitor cell (prosensory cell) proliferation and differentiation result in abnormal cellular organization and, thus, auditory dysfunction. The molecular mechanisms involved in the timing and coordination of auditory prosensory proliferation and differentiation are poorly understood. Here we identify the RNA-binding protein LIN28B as a critical regulator of developmental timing in the murine cochlea. We show that Lin28b and its opposing let-7 miRNAs are differentially expressed in the auditory sensory lineage, with Lin28b being highly expressed in undifferentiated prosensory cells and let-7 miRNAs being highly expressed in their progeny-hair cells (HCs) and supporting cells (SCs). Using recently developed transgenic mouse models for LIN28B and let-7g, we demonstrate that prolonged LIN28B expression delays prosensory cell cycle withdrawal and differentiation, resulting in HC and SC patterning and maturation defects. Surprisingly, let-7g overexpression, although capable of inducing premature prosensory cell cycle exit, failed to induce premature HC differentiation, suggesting that LIN28B's functional role in the timing of differentiation uses let-7 independent mechanisms. Finally, we demonstrate that overexpression of LIN28B or let-7g can significantly alter the postnatal production of HCs in response to Notch inhibition; LIN28B has a positive effect on HC production, whereas let-7 antagonizes this process. Together, these results implicate a key role for the LIN28B/let-7 axis in regulating postnatal SC plasticity. KEYWORDS: Let-7; Lin28b; cochlea; hair cell; regeneration

PMID 26139524

Signaling regulating inner ear development: cell fate determination, patterning, morphogenesis, and defects

Congenit Anom (Kyoto). 2015 Feb;55(1):17-25. doi: 10.1111/cga.12072.

Nakajima Y1.


The membranous labyrinth of the inner ear is a highly complex organ that detects sound and balance. Developmental defects in the inner ear cause congenital hearing loss and balance disorders. The membranous labyrinth consists of three semicircular ducts, the utricle, saccule, and endolymphatic ducts, and the cochlear duct. These complex structures develop from the simple otic placode, which is established in the cranial ectoderm adjacent to the neural crest at the level of the hindbrain at the early neurula stage. During development, the otic placode invaginates to form the otic vesicle, which subsequently gives rise to neurons for the vestibulocochlear ganglion, the non-sensory and sensory epithelia of the membranous labyrinth that includes three ampullary crests, two maculae, and the organ of Corti. Combined paracrine and autocrine signals including fibroblast growth factor, Wnt, retinoic acid, hedgehog, and bone morphogenetic protein regulate fate determination, axis formation, and morphogenesis in the developing inner ear. Juxtacrine signals mediated by Notch pathways play a role in establishing the sensory epithelium, which consists of mechanosensory hair cells and supporting cells. The highly differentiated organ of Corti, which consists of uniformly oriented inner/outer hair cells and specific supporting cells, develops during fetal development. Developmental alterations/arrest causes congenital malformations in the inner ear in a spatiotemporal-restricted manner. A clearer understanding of the mechanisms underlying inner ear development is important not only for the management of patients with congenital inner ear malformations, but also for the development of regenerative therapy for impaired function. © 2014 Japanese Teratology Society. KEYWORDS: Notch; development; growth factors; inner ear; malformations

PMID 25040109

Development of the inner ear

Curr Opin Genet Dev. 2015 Mar 18;32:112-118. doi: 10.1016/j.gde.2015.02.006.

Whitfield TT1.


The vertebrate inner ear is a sensory organ of exquisite design and sensitivity. It responds to sound, gravity and movement, serving both auditory (hearing) and vestibular (balance) functions. Almost all cell types of the inner ear, including sensory hair cells, sensory neurons, secretory cells and supporting cells, derive from the otic placode, one of the several ectodermal thickenings that arise around the edge of the anterior neural plate in the early embryo. The developmental patterning mechanisms that underlie formation of the inner ear from the otic placode are varied and complex, involving the reiterative use of familiar signalling pathways, together with roles for transcription factors, transmembrane proteins, and extracellular matrix components. In this review, I have selected highlights that illustrate just a few of the many recent discoveries relating to the development of this fascinating organ system. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

PMID 25796080

© 2015 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY license (

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

Dev Neurobiol. 2015 Feb 7. doi: 10.1002/dneu.22279.

Locher H1, de Groot JC, van Iperen L, Huisman MA, Frijns JH, Chuva de Sousa Lopes SM.


Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9-W18) and show the cochlear expression dynamics of key potassium-regulating proteins. At W12, MITF+/SOX10+/KIT+ neural-crest-derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+ /K+ -ATPase-positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol, 2015. © 2015 The Authors Developmental Neurobiology Published by Wiley Periodicals, Inc. KEYWORDS: development; human; melanocytes; sensorineural hearing loss; stria vascularis

PMID 25663387


Distribution and development of peripheral glial cells in the human fetal cochlea

PLoS One. 2014 Jan 31;9(1):e88066. doi: 10.1371/journal.pone.0088066. eCollection 2014.

Locher H1, de Groot JC2, van Iperen L3, Huisman MA2, Frijns JH2, Chuva de Sousa Lopes SM4.


The adult human cochlea contains various types of peripheral glial cells that envelop or myelinate the three different domains of the spiral ganglion neurons: the central processes in the cochlear nerve, the cell bodies in the spiral ganglia, and the peripheral processes in the osseous spiral lamina. Little is known about the distribution, lineage separation and maturation of these peripheral glial cells in the human fetal cochlea. In the current study, we observed peripheral glial cells expressing SOX10, SOX9 and S100B as early as 9 weeks of gestation (W9) in all three neuronal domains. We propose that these cells are the common precursor to both mature Schwann cells and satellite glial cells. Additionally, the peripheral glial cells located along the peripheral processes expressed NGFR, indicating a phenotype distinct from the peripheral glial cells located along the central processes. From W12, the spiral ganglion was gradually populated by satellite glial cells in a spatiotemporal gradient. In the cochlear nerve, radial sorting was accomplished by W22 and myelination started prior to myelination of the peripheral processes. The developmental dynamics of the peripheral glial cells in the human fetal cochlea is in support of a neural crest origin. Our study provides the first overview of the distribution and maturation of peripheral glial cells in the human fetal cochlea from W9 to W22.

PMID 24498246

Development of the innervation of the human inner ear

Dev Neurobiol. 2014 Nov 1. doi: 10.1002/dneu.22242. [Epub ahead of print]

Pechriggl EJ1, Bitsche M, Glueckert R, Rask-Andersen H, Blumer MJ, Schrott-Fischer A, Fritsch H.


Studies on the formation of neuronal structures of the human cochlea are rare, presumptively, due to the difficult accessibility of specimens, so that most investigations are performed on mouse models. By means of immunohistochemical and transmission electron microscopic techniques we investigated an uninterrupted series of unique specimens from gestational week 8 to week 12. We were able to demonstrate the presence of nerve fibers in the prosensory domain at embryonic week 8, followed by afferent synaptogenesis at week 11. We identified PAX2 as an early marker for hair cell differentiation. Glutamine synthetase-positive peripheral glial cells occurred at the beginning of week 8. Transcription factor MAF B was utilized to demonstrate maturation of the spiral ganglion neurons. The early expression of tyrosine hydroxylase could be assessed. This study provides insights in the early assembly of the neural circuit and organization in humans. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014. Copyright © 2014 Wiley Periodicals, Inc., a Wiley company. KEYWORDS: BDNF; Glutamine Synthetase; MAF B; PAX2; early development; inner ear; innervation

PMID 25363666

Junctionally restricted RhoA activity is necessary for apical constriction during phase 2 inner ear placode invagination

Dev Biol. 2014 Oct 15;394(2):206-16. doi: 10.1016/j.ydbio.2014.08.022. Epub 2014 Aug 28.

Sai X1, Yonemura S2, Ladher RK3.


After induction, the inner ear is transformed from a superficially located otic placode into an epithelial vesicle embedded in the mesenchyme of the head. Invagination of this epithelium is biphasic: phase 1 involves the expansion of the basal aspect of the otic cells, and phase 2, the constriction of their apices. Apical constriction is important not only for otic invagination, but also the invagination of many other epithelia; however, its molecular basis is still poorly understood. Here we show that phase 2 otic morphogenesis, like phase 1 morphogenesis, results from the activation of myosin-II. However unlike the actin depolymerising activity observed basally, active myosin-II results in actomyosin contractility. Myosin-II activation is triggered by the accumulation of the planar cell polarity (PCP) core protein, Celsr1 in apical junctions (AJ). Apically polarized Celsr1 orients and recruits the Rho Guanine exchange factor (GEF) ArhGEF11 to apical junctions, thus restricting RhoA activity to the junctional membrane where it activates the Rho kinase ROCK. We suggest that myosin-II and RhoA activation results in actomyosin dependent constriction in an apically polarised manner driving otic epithelium invagination. Copyright © 2014 Elsevier Inc. All rights reserved. KEYWORDS: Inner ear; Invagination; Morphogenesis; Myosin-II; Placode; RhoA

PMID 25173873

Kölliker's organ and the development of spontaneous activity in the auditory system: implications for hearing dysfunction

Biomed Res Int. 2014;2014:367939. doi: 10.1155/2014/367939. Epub 2014 Aug 20.

Dayaratne MW1, Vlajkovic SM1, Lipski J1, Thorne PR2.


Prior to the "onset of hearing," developing cochlear inner hair cells (IHCs) and primary auditory neurons undergo experience-independent activity, which is thought to be important in retaining and refining neural connections in the absence of sound. One of the major hypotheses regarding the origin of such activity involves a group of columnar epithelial supporting cells forming Kölliker's organ, which is only present during this critical period of auditory development. There is strong evidence for a purinergic signalling mechanism underlying such activity. ATP released through connexin hemichannels may activate P2 purinergic receptors in both Kölliker's organ and the adjacent IHCs, leading to generation of electrical activity throughout the auditory system. However, recent work has suggested an alternative origin, by demonstrating the ability of IHCs to generate this spontaneous activity without activation by ATP. Regardless, developmental abnormalities of Kölliker's organ may lead to congenital hearing loss, considering that mutations in ion channels (hemichannels, gap junctions, and calcium channels) involved in Kölliker's organ activity share strong links with such types of deafness. PMID 25210710

Distribution and development of peripheral glial cells in the human fetal cochlea

PLoS One. 2014 Jan 31;9(1):e88066. doi: 10.1371/journal.pone.0088066. eCollection 2014.

Locher H1, de Groot JC2, van Iperen L3, Huisman MA2, Frijns JH2, Chuva de Sousa Lopes SM4. Author information


The adult human cochlea contains various types of peripheral glial cells that envelop or myelinate the three different domains of the spiral ganglion neurons: the central processes in the cochlear nerve, the cell bodies in the spiral ganglia, and the peripheral processes in the osseous spiral lamina. Little is known about the distribution, lineage separation and maturation of these peripheral glial cells in the human fetal cochlea. In the current study, we observed peripheral glial cells expressing SOX10, SOX9 and S100B as early as 9 weeks of gestation (W9) in all three neuronal domains. We propose that these cells are the common precursor to both mature Schwann cells and satellite glial cells. Additionally, the peripheral glial cells located along the peripheral processes expressed NGFR, indicating a phenotype distinct from the peripheral glial cells located along the central processes. From W12, the spiral ganglion was gradually populated by satellite glial cells in a spatiotemporal gradient. In the cochlear nerve, radial sorting was accomplished by W22 and myelination started prior to myelination of the peripheral processes. The developmental dynamics of the peripheral glial cells in the human fetal cochlea is in support of a neural crest origin. Our study provides the first overview of the distribution and maturation of peripheral glial cells in the human fetal cochlea from W9 to W22.

PMID 24498246


Neurosensory development and cell fate determination in the human cochlea

Neural Dev. 2013 Oct 16;8:20. doi: 10.1186/1749-8104-8-20.

Locher H, Frijns JH, van Iperen L, de Groot JC, Huisman MA, Chuva de Sousa Lopes SM1.


BACKGROUND: Hearing depends on correct functioning of the cochlear hair cells, and their innervation by spiral ganglion neurons. Most of the insight into the embryological and molecular development of this sensory system has been derived from animal studies. In contrast, little is known about the molecular expression patterns and dynamics of signaling molecules during normal fetal development of the human cochlea. In this study, we investigated the onset of hair cell differentiation and innervation in the human fetal cochlea at various stages of development. RESULTS: At 10 weeks of gestation, we observed a prosensory domain expressing SOX2 and SOX9/SOX10 within the cochlear duct epithelium. In this domain, hair cell differentiation was consistently present from 12 weeks, coinciding with downregulation of SOX9/SOX10, to be followed several weeks later by downregulation of SOX2. Outgrowing neurites from spiral ganglion neurons were found penetrating into the cochlear duct epithelium prior to hair cell differentiation, and directly targeted the hair cells as they developed. Ubiquitous Peripherin expression by spiral ganglion neurons gradually diminished and became restricted to the type II spiral ganglion neurons by 18 weeks. At 20 weeks, when the onset of human hearing is thought to take place, the expression profiles in hair cells and spiral ganglion neurons matched the expression patterns of the adult mammalian cochleae. CONCLUSIONS: Our study provides new insights into the fetal development of the human cochlea, contributing to our understanding of deafness and to the development of new therapeutic strategies to restore hearing.

PMID 24131517

Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea

Development. 2013 Sep;140(18):3848-57. doi: 10.1242/dev.095398. Epub 2013 Aug 14.

Tateya T, Imayoshi I, Tateya I, Hamaguchi K, Torii H, Ito J, Kageyama R. Author information

Abstract Mechanosensory hair cells and supporting cells develop from common precursors located in the prosensory domain of the developing cochlear epithelium. Prosensory cell differentiation into hair cells or supporting cells proceeds from the basal to the apical region of the cochleae, but the mechanism and significance of this basal-to-apical wave of differentiation remain to be elucidated. Here, we investigated the role of Hedgehog (Hh) signaling in cochlear development by examining the effects of up- and downregulation of Hh signaling in vivo. The Hh effector smoothened (Smo) was genetically activated or inactivated specifically in the developing cochlear epithelium after prosensory domain formation. Cochleae expressing a constitutively active allele of Smo showed only one row of inner hair cells with no outer hair cells (OHCs); abnormal undifferentiated prosensory-like cells were present in the lateral compartment instead of OHCs and their adjacent supporting cells. This suggests that Hh signaling inhibits prosensory cell differentiation into hair cells or supporting cells and maintains their properties as prosensory cells. Conversely, in cochlea with the Smo conditional knockout (Smo CKO), hair cell differentiation was preferentially accelerated in the apical region. Smo CKO mice survived after birth, and exhibited hair cell disarrangement in the apical region, a decrease in hair cell number, and hearing impairment. These results indicate that Hh signaling delays hair cell and supporting cell differentiation in the apical region, which forms the basal-to-apical wave of development, and is required for the proper differentiation, arrangement and survival of hair cells and for hearing ability. KEYWORDS: Cochlea, Hair cells, Hedgehog signaling, Mouse instigate

PMID 23946445

Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells

Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13869-74. doi: 10.1073/pnas.1222341110. Epub 2013 Aug 5.

Bok J, Zenczak C, Hwang CH, Wu DK. Author information

Abstract Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissue-specific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation.

PMID 23918393


Dual embryonic origin of the mammalian otic vesicle forming the inner ear

Development. 2011 Dec;138(24):5403-14. doi: 10.1242/dev.069849.

Freyer L1, Aggarwal V, Morrow BE.


The inner ear and cochleovestibular ganglion (CVG) derive from a specialized region of head ectoderm termed the otic placode. During embryogenesis, the otic placode invaginates into the head to form the otic vesicle (OV), the primordium of the inner ear and CVG. Non-autonomous cell signaling from the hindbrain to the OV is required for inner ear morphogenesis and neurogenesis. In this study, we show that neuroepithelial cells (NECs), including neural crest cells (NCCs), can contribute directly to the OV from the neural tube. Using Wnt1-Cre, Pax3(Cre/+) and Hoxb1(Cre/+) mice to label and fate map cranial NEC lineages, we have demonstrated that cells from the neural tube incorporate into the otic epithelium after otic placode induction has occurred. Pax3(Cre/+) labeled a more extensive population of NEC derivatives in the OV than did Wnt1-Cre. NEC derivatives constitute a significant population of the OV and, moreover, are regionalized specifically to proneurosensory domains. Descendents of Pax3(Cre/+) and Wnt1-Cre labeled cells are localized within sensory epithelia of the saccule, utricle and cochlea throughout development and into adulthood, where they differentiate into hair cells and supporting cells. Some NEC derivatives give rise to neuroblasts in the OV and CVG, in addition to their known contribution to glial cells. This study defines a dual cellular origin of the inner ear from sensory placode ectoderm and NECs, and changes the current paradigm of inner ear neurosensory development.

PMID 22110056

Rbpj regulates development of prosensory cells in the mammalian inner ear

Dev Biol. 2011 Mar 21. [Epub ahead of print]

Yamamoto N, Chang W, Kelley MW.

Laboratory of Cochlear Development, National Institute on Deafness and other Communication Disorders, National Institutes of Health, NIDCD, NIH, Bethesda, MD 20892, USA; Department of Otolaryngology Head and Neck Surgery, Graduate School of Medicine, Kyoto University Sakyo-ku, Kyoto, 606-8507, Kyoto, Japan. Abstract The vertebrate inner ear contains multiple sensory patches comprised of hair cells and supporting cells. During development these sensory patches arise from prosensory cells that are specified and maintained through the expression of specific molecular factors. Disruption of Jagged1-mediated notch signaling causes a loss of some sensory patches and disruptions in others, indicating a role in some aspect of prosensory development. However, the presence of some sensory patches suggests that some level of notch activity persists in the absence of Jagged1. Therefore, the transcription factor Rbpj, which is required for nearly all notch function, was deleted in the developing otocyst. Results indicate a nearly complete absence of all prosensory patches in the inner ear with remaining hair cells located predominantly in the extreme apex of the cochlea. However, early markers of prosensory cells are still present in Rbpj-mutants, suggesting that maintenance, rather than induction, of prosensory development is dependent on notch signaling. Moreover, analysis of developing cochleae in Rbpj-mutants indicates changes in the spatiotemporal patterns of expression for p27(kip1), Atoh1 and hair cell differentiation markers implicating notch signaling in the regulation of the timing of cellular differentiation and/or in the maintenance of a stem/progenitor cell stage. Finally, the absence of Rbpj caused increased cell death in the cochlea beginning at E12. These results suggest important roles for Rbpj and notch signaling in multiple aspects of inner ear development including prosensory cell maturation, cellular differentiation and survival.

Copyright © 2011. Published by Elsevier Inc.

PMID 21420948

Development of tonotopy in the auditory periphery

Hear Res. 2011 Jan 27. [Epub ahead of print]

Mann ZF, Kelley MW.

Laboratory of Cochlear Development, NIDCD, NIH, Bethesda, MD 20892, USA.

Abstract Acoustic frequency analysis plays an essential role in sound perception, communication and behavior. The auditory systems of most vertebrates that perceive sounds in air are organized based on the separation of complex sounds into component frequencies. This process begins at the level of the auditory sensory epithelium where specific frequencies are distributed along the tonotopic axis of the mammalian cochlea or the avian/reptilian basilar papilla (BP). Mechanical and electrical mechanisms mediate this process, but the relative contribution of each mechanism differs between species. Developmentally, structural and physiological specializations related to the formation of a tonotopic axis form gradually over an extended period of time. While some aspects of tonotopy are evident at early stages of auditory development, mature frequency discrimination is typically not achieved until after the onset of hearing. Despite the importance of tonotopic organization, the factors that specify unique positional identities along the cochlea or basilar papilla are unknown. However, recent studies of developing systems, including the inner ear provide some clues regarding the signalling pathways that may be instructive for the formation of a tonotopic axis.

Published by Elsevier B.V.

PMID 21276841


From shared lineage to distinct functions: the development of the inner ear and epibranchial placodes.

Development. 2010 Jun;137(11):1777-85.

Ladher RK, O'Neill P, Begbie J.

RIKEN Center for Developmental Biology, Chuoku, Kobe 650-0047, Japan. Abstract The inner ear and the epibranchial ganglia constitute much of the sensory system in the caudal vertebrate head. The inner ear consists of mechanosensory hair cells, their neurons, and structures necessary for sound and balance sensation. The epibranchial ganglia are knots of neurons that innervate and relay sensory signals from several visceral organs and the taste buds. Their development was once thought to be independent, in line with their independent functions. However, recent studies indicate that both systems arise from a morphologically distinct common precursor domain: the posterior placodal area. This review summarises recent studies into the induction, morphogenesis and innervation of these systems and discusses lineage restriction and cell specification in the context of their common origin.

A symphony of inner ear developmental control genes

BMC Genet. 2010 Jul 16;11:68.

Chatterjee S, Kraus P, Lufkin T.

Stem Cell and Developmental Biology, Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore. Abstract The inner ear is one of the most complex and detailed organs in the vertebrate body and provides us with the priceless ability to hear and perceive linear and angular acceleration (hence maintain balance). The development and morphogenesis of the inner ear from an ectodermal thickening into distinct auditory and vestibular components depends upon precise temporally and spatially coordinated gene expression patterns and well orchestrated signaling cascades within the otic vesicle and upon cellular movements and interactions with surrounding tissues. Gene loss of function analysis in mice has identified homeobox genes along with other transcription and secreted factors as crucial regulators of inner ear morphogenesis and development. While otic induction seems dependent upon fibroblast growth factors, morphogenesis of the otic vesicle into the distinct vestibular and auditory components appears to be clearly dependent upon the activities of a number of homeobox transcription factors. The Pax2 paired-homeobox gene is crucial for the specification of the ventral otic vesicle derived auditory structures and the Dlx5 and Dlx6 homeobox genes play a major role in specification of the dorsally derived vestibular structures. Some Micro RNAs have also been recently identified which play a crucial role in the inner ear formation.

PMID 20637105

New insight into the bony labyrinth: a microcomputed tomography study

Richard C, Laroche N, Malaval L, Dumollard JM, Martin Ch, Peoch M, Vico L, Prades JM. Auris Nasus Larynx. 2010 Apr;37(2):155-61. Epub 2009 Jul 4. PMID: 19577870

"Our findings show different rates of growth among the semicircular canals, the vestibular aqueduct, the oval window, the round window and the cochlea. The final sizes of the cochlea and round window are achieved at 23 weeks of gestation, with heights of 5mm and 2mm, respectively. The oval window reaches adult size at 35 weeks, whereas the vestibular aqueduct will attain adult size after birth. An increasing degree of torsion of each semicircular canal is observed during fetal development. The superior semicircular canal achieves adult size at 24 weeks, before the posterior and the lateral canals (25 weeks). The time-course of ossification and mineralization observed in structures and confirmed by histology. CONCLUSIONS: During this developmental period poorly studied until now, our findings suggest that each part of the bony labyrinth follows distinct growth and ossification kinetics trajectories, some of these reaching their adult size only after birth. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved."


Development of form and function in the mammalian cochlea.

Kelly MC, Chen P. Curr Opin Neurobiol. 2009 Aug;19(4):395-401. Epub 2009 Aug 15. Review. PMID 19683914

On the number of turns in human cochleae

Otol Neurotol. 2009 Apr;30(3):414-7. doi: 10.1097/MAO.0b013e3181977b8d. Biedron S1, Westhofen M, Ilgner J.

Abstract OBJECTIVE: The number of human cochlear turns is generally accepted being 2 1/2, although cases with up to 2 3/4 or even 3 turns are known from literature. This study was performed to evaluate the actual number of cochlear turns and its variance. METHODS: Histologic temporal bone series from the "Wittmaack temporal bone collection" (Hamburg, Germany) were examined, and the number of scala media segments was counted using the midmodiolar sections. These data were evaluated in reference to the cochlear spiral to obtain the number of cochlear turns. RESULTS: Sixty-five percent of the investigated specimens had more than 2 1/2 cochlear turns, of which, 11% had more than 2 3/4 turns. CONCLUSION: The number of human cochlear turns shows a higher variance than is represented in literature. Cases with up to 3 turns can be regarded as upper limit of the normal range. This finding may carry further implications for cochlear implantation to focus on the development of individually shaped electrode carriers and stimulation strategies. PMID 19225438

Collagen-based mechanical anisotropy of the tectorial membrane: implications for inter-row coupling of outer hair cell bundles

PLoS One. 2009;4(3):e4877. Epub 2009 Mar 18.

Gavara N, Chadwick RS.

Auditory Mechanics Section, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA. Abstract BACKGROUND: The tectorial membrane (TM) in the mammalian cochlea displays anisotropy, where mechanical or structural properties differ along varying directions. The anisotropy arises from the presence of collagen fibrils organized in fibers of approximately 1 microm diameter that run radially across the TM. Mechanical coupling between the TM and the sensory epithelia is required for normal hearing. However, the lack of a suitable technique to measure mechanical anisotropy at the microscale level has hindered understanding of the TM's precise role.

METHODOLOGY/PRINCIPAL FINDINGS: Here we report values of the three elastic moduli that characterize the anisotropic mechanical properties of the TM. Our novel technique combined Atomic Force Microscopy (AFM), modeling, and optical tracking of microspheres to determine the elastic moduli. We found that the TM's large mechanical anisotropy results in a marked transmission of deformations along the direction that maximizes sensory cell excitation, whereas in the perpendicular direction the transmission is greatly reduced.

CONCLUSIONS/SIGNIFICANCE: Computational results, based on our values of elastic moduli, suggest that the TM facilitates the directional cooperativity of sensory cells in the cochlea, and that mechanical properties of the TM are tuned to guarantee that the magnitude of sound-induced tip-link stretching remains similar along the length of the cochlea. Furthermore, we anticipate our assay to be a starting point for other studies of biological tissues that require directional functionality.

PMID 19293929

Masculinization of the mammalian cochlea

McFadden D. Department of Psychology and Center for Perceptual Systems, University of Texas at Austin, Seay Building, 1 University Station, A8000, Austin, TX 78712-0187, USA. Abstract Otoacoustic emissions (OAEs) differ between the sexes in humans, rhesus and marmoset monkeys, and sheep. OAEs also are different in a number of special populations of humans. Those basic findings are reviewed and discussed in the context of possible prenatal-androgen effects on the auditory system. A parsimonious explanation for several outcomes is that prenatal exposure to high levels of androgens can weaken the cochlear amplifiers and thereby weaken otoacoustic emissions (OAEs). Prenatal androgen exposure apparently also can alter auditory evoked potentials (AEPs). Some non-hormonal factors possibly capable of producing sex and group differences are discussed, and some speculations are offered about specific cochlear structures that might differ between the two sexes. PMID: 19272340

Specification of cell fate in the mammalian cochlea

Birth Defects Res C Embryo Today. 2009 Sep;87(3):212-21. Driver EC, Kelley MW.

Section on Developmental Neuroscience, National Institute on Deafness and other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA. Abstract Mammalian auditory sensation is mediated by the organ of Corti, a specialized sensory epithelium found in the cochlea of the inner ear. Proper auditory function requires that the many different cell types found in the sensory epithelium be precisely ordered within an exquisitely patterned cellular mosaic. The development of this mosaic depends on a series of cell fate decisions that transform the initially nearly uniform cochlear epithelium into the complex structure of the mature organ of Corti. The prosensory domain, which contains the progenitors of both the mechanosensory hair cells and their associated supporting cells, first becomes distinct from both the neural and the nonsensory domains. Further cell fate decisions subdivide prosensory cells into populations of inner and outer hair cells, and several different types of supporting cells. A number of different signaling pathways and transcription factors are known to be necessary for these developmental processes; in this review, we will summarize these results with an emphasis on recent findings.

PMID 19750520


Science and life--the history of Marquis Alfonso Corti

(Article in Polish)

Otolaryngol Pol. 2008;62(3):344-7. doi: 10.1016/S0030-6657(08)70268-3.

Betlejewski S.


Alfonso Corti was born at Gambarana, near Pavia in 1822. A famous friend of Corti's father, Antonio Scarpa, may have kindled his boyhood interest in anatomy and medicine. As a medical student he enrolled first at the University of Pavia. Corti's favorite study there was microanatomy with Bartolomeo Panizza and Mario Rusconi. In 1845, against paternal wishes, Corti moved to Vienna to complete his medical studies and to work in the anatomical institute of Joseph Hirtl. There he received the degree in medicine in 1847 under the supervision of professor Hyrtl, with a thesis on the bloodstream system of a reptile. He was then appointed by Hyrtl to be his Second Prosector. With the outbreak of the 1848 Revolution he left Vienna, and after brief military service in Italy made visits to eminent scientist in Bern, London and Paris. By the beginning of 1850 Corti had received the invitation of the anatomist Albert Kölliker and had moved to Würzburg, where he made friends with Virchow. At the Kölliker Laboratory he began to work on the mammalian auditory system. A short time Corti spent in Utrecht, where he visited Professors Schroeder van der Kolk and Pieter Harting. In Utrecht Corti learned to use methods to preserve several preparations of the cochlea. From Utrecht he returned to Würzburg to complete his study of at least 200 cochlea's' of man and different animals. His famous paper: "Recherches sur l'organe de l'ouïe des mammiferes" appeared in 1851 in Kölliker's journal "Zeitschrift für wissenschaftliche Zoologie". In the same year, after death of his father, he inherited father's title Marchese de San Stefano Belbo and estate and moved back to Italy. In 1855 Corti married the daughter from a neighboring estate, Maria Bettinzoli. His young wife presented him with a daughter Bianca, and a son Gaspare, but in 1861 she died, leaving him with the responsibility of rearing the children. Unfortunately he was gradually developing arthritis deformans. Corti's last 15 years were further darkened by the inexorable progress of his crippling illness. In 1876, on the second of October, he died at Corvino San Quirico. PMID 18652163


An actin molecular treadmill and myosins maintain stereocilia functional architecture and self-renewal

J Cell Biol. 2004 Mar 15;164(6):887-97.

Rzadzinska AK, Schneider ME, Davies C, Riordan GP, Kachar B. Source Section on Structural Cell Biology, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bldg. 50/Rm. 4249, 50 South Dr., Bethesda, MD 20892-8027, USA.


We have previously shown that the seemingly static paracrystalline actin core of hair cell stereocilia undergoes continuous turnover. Here, we used the same approach of transfecting hair cells with actin-green fluorescent protein (GFP) and espin-GFP to characterize the turnover process. Actin and espin are incorporated at the paracrystal tip and flow rearwards at the same rate. The flux rates (approximately 0.002-0.04 actin subunits s(-1)) were proportional to the stereocilia length so that the entire staircase stereocilia bundle was turned over synchronously. Cytochalasin D caused stereocilia to shorten at rates matching paracrystal turnover. Myosins VI and VIIa were localized alongside the actin paracrystal, whereas myosin XVa was observed at the tips at levels proportional to stereocilia lengths. Electron microscopy analysis of the abnormally short stereocilia in the shaker 2 mice did not show the characteristic tip density. We argue that actin renewal in the paracrystal follows a treadmill mechanism, which, together with the myosins, dynamically shapes the functional architecture of the stereocilia bundle.

PMID 15024034

Good sem and fluro pictures of hair cell stereo cilia.


Embryonic development of the human organ of Corti: electron microscopic study

Int J Pediatr Otorhinolaryngol. 1980 Apr;2(1):51-62.

Igarashi Y, Ishii T.


A morphological approach by the electron microscope was used to obtain findings suggestive of the onset of auditory function in the fetal human cochlea. The organs of Corti at three different embryonic ages: 20 weeks 3 days, 22 weeks, and 24 weeks, were studied from the following standpoints: auditory hairs; hair cell bodies; the interrelationship between sensory cells and supporting cells; fluid spaces in the organ of Corti; and nerve endings to the sensory cells. Assessment of these findings implies that the peripheral auditory organ is ready for sending afferent impulses at around 24 weeks of embryonic age.

PMID 7188054

  • stria vascularis - GA 20 week 3 days - 22 week
  • sectorial membrane - GA 20 week 3 days
  • tunnel of corti - GA 24 week 0 days
  • Nuel space - GA 22 week 0 days - 24 week
  • Space between hair and supporting cell - 24 week
  • Afferent nerve ending - GA 20 week 3 days
  • Efferent nerve ending - GA 22 week 0 days
  • Presence of kinocilium - GA 24 week 0 days
  • Maturation of stereocilia - GA 22 week 0 days - 24 week 0 days
Organ of Corti GA age Fertilisation age
Structure (weeks.days} (weeks.days}
stria vascularis 20.3 - 22 18.3 - 20
sectorial membrane 20.3 18.3
tunnel of corti 24 22
nuel space 22 - 24 20 - 22
supporting and hair cell space 24 22
afferent nerve ending 20.3 18.3
efferent nerve ending 22 20
kinocilium 24 22
maturation of stereocilia 22 - 24 20 - 22
PMID 7188054