Talk:Hearing - Inner Ear Development

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Cite this page: Hill, M.A. (2019, December 7) Embryology Hearing - Inner Ear Development. Retrieved from


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


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

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.