Neurosensory development and cell fate determination in the human cochlea
© Locher et al.; licensee BioMed Central Ltd. 2013
Received: 30 August 2013
Accepted: 20 September 2013
Published: 16 October 2013
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.
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.
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.
KeywordsHuman Fetus Cochlea SOX transcription factors Hair cells Spiral ganglion Innervation Peripherin
The cochlea houses two of the main cell types responsible for hearing: the hair cells and the spiral ganglion neurons (SGNs). Damage to the cochlea is usually associated with degeneration and irreversible loss of these cell types, which ultimately leads to permanent sensorineural hearing loss, the most common type of deafness [1, 2]. In order to develop new therapeutic strategies, it is essential to have a better understanding of the normal molecular development of the human cochlea.
In the human embryo, the otic placode invaginates to form the otic vesicle (or otocyst) during week 6 of gestation (W6), equivalent to week 4 of fetal development . In the subsequent weeks, the otic vesicle develops into both the vestibular organs and the cochlea. The cochlear duct spirals around a central axis, and reaches its final 2.5 turns by W10 to W11 [4, 5]. At this stage, the epithelial lining of the cochlear duct is still undifferentiated. In mice, a dedicated area within the epithelium of the cochlear duct floor has been identified as the 'prosensory domain’ ; this contains the precursors to the inner hair cells (IHCs), the outer hair cells (OHCs), and various types of surrounding supporting cells, which together form the organ of Corti (OC) [7, 8]. The prosensory domain is flanked by two other domains: Kölliker’s organ (KO) and the future outer sulcus. Although the prosensory domain has not been formally described in humans, hair cells are first visible by W12 in the human fetus in the region where the OC will form . The OC reaches its gross adult morphology around W20, which corresponds to the onset of auditory function [9–11].
Development of the prosensory domain into the OC coincides with the establishment of highly specialized innervation patterns by afferent type I and type II SGNs. In humans, multiple type I SGNs innervate single IHCs in a 'radial’ organization, and make up 90 to 95% of the total population of SGNs, whereas single type II SGNs contact multiple OHCs in a 'spiral’ organization . In mice, SGNs project to both IHCs and OHCs until 6 to 7 days after birth, when a clear distinction between type I and type II ganglion neurons takes place, just prior to the onset of hearing (post-natal week 2) [13, 14]. In humans, penetration of the SGN neurites into the cochlear neuroepithelium has been observed earlier than the first differentiation of hair cells by electron microscopy . The peripheral neurites of the SGNs penetrate the basal turn around W11, and in the following weeks find their way to the developing hair cells and shape their synaptic connections [5, 15]. However, the separation of type I and type II SGNs has not been investigated in humans.
Here, we investigated both the dynamics of development of human cochlear hair cells and their innervation. The spatial and temporal dynamics of hair cell differentiation was determined by examining the expression of three members of the SOX family, a group of genes involved with cell fate decisions: SOX2, SOX9, and SOX10. An example of early cell fate specification in the cochlear duct epithelium is the spatially restricted expression of SOX2 to the cells of the prosensory domain . The functional importance of the SOX2 transcription factor in normal cochlear development is further illustrated by failure of the prosensory domain establishment in loss-of-function conditions , and underdevelopment of hair cells in gain-of-function conditions . Sox9 and Sox10 are known to be expressed in the otic placode and the otic vesicle in frog and chick [17–20]. In mice, SOX9 is also expressed in the otic placode and otic vesicle and controls invagination , and both SOX9 and SOX10 have been found in the mouse cochlear duct epithelium [22–26]. Interestingly, in mice, Sox9 and Sox10 are downregulated before or upon hair cell differentiation, whereas Sox2 is downregulated gradually, although all three Sox genes remain expressed in the underlying supporting cells in the OC [8, 22, 23].
In humans, SOX2, SOX9, and SOX10 are likely to play an important role in cochlear development, as mutations in all three genes have been shown to cause sensorineural hearing loss [27–29]. However, although SOX10 expression has been reported in the human otic vesicle , expression patterns of these SOX transcription factors, and their dynamics upon hair cell differentiation, have not previously been determined in the (developing) human cochlea. In addition, the innervation of the IHCs and OHCs was in the current study investigated by comparing the dynamics of expression of Peripherin (PRPH), an intermediate filament protein that is expressed in type II SGNs, both in adult mouse and adult human cochleae [13, 31], along with the expression of class III β-Tubulin (TUBB3), a general SGN marker. The comprehensive description of the molecular and morphological events taking place in the cochlea as functional hearing develops may benefit the development of strategies for cochlear repair.
The human prosensory domain is SOX2-positive
Differentiating cochlear hair cells downregulated SOX9 and SOX10, followed by SOX2
At W12, the openings of the scala vestibuli and the scala tympani were observed, respectively, above and beneath the basal turn of the cochlear duct (Figure 1D). The first morphological signs of hair cell differentiation were then visible exclusively in the basal turn, as a row of single cells that emerged facing the luminal aspect of the SOX2-positive prosensory domain (Figure 1D, E). Immunostaining for myosin VIIA (MYO7A), a marker of hair cells, confirmed this lineage specification (Figure 1F). Based on the position of the first hair cells at the border between the prosensory domain (SOX2-positive) and Kölliker’s organ (SOX2-negative), we identified these cells as IHCs (Figure 1E) and found that lineage specification to IHCs coincided with downregulation of SOX9 (Figure 1F).
Innervation of the cochlear duct by PRPH-positive neurites precedes hair cell differentiation
As at W10.4, both PRPH-positive and TUBB3-positive neurites where still located directly below the prosensory domain in the W12 apical turn, (Figure 5C). However, high magnification scanning revealed the presence of PRPH-positive and TUBB3-positive growth cones extending a few micrometers into the cochlear epithelium (Figure 5C′, white and black arrows, respectively), suggesting that in humans, neurites penetrate the basement membrane prior to signs of hair cell differentiation, as confirmed by the lack of MYO7A (Figure 5D).
In the W12 middle turn, innervation by both PRPH and TUBB3 positive neurites advanced further into the epithelium (Figure 5E). These neurites penetrated the basement membrane at multiple positions directly below the reorganizing prosensory domain, and seemed directed predominantly toward one specific cell type, most probably the first future hair cell to emerge, as the prosensory domain remained MYO7A-negative (Figure 5F).
In the W12 basal turn, the neurites progressed upwards along different routes and contacted the base of the first differentiated MYO7A-positive hair cells, identified here as IHCs, at multiple positions along its basal side (Figure 5G,H). Many neurites seemed to express both PRPH and TUBB3. Strikingly, single neurites positive for both PRPH and TUBB3 invaded the epithelium at a more lateral position, at the site of the future OHCs (Figure 5G, yellow arrow), suggesting that innervation into the future OHC area precedes OHC differentiation, just as innervation into the IHC area precedes IHC differentiation.
PRPH-positive neurites become restricted to the OHC by W20.3
Additional file 1: Movie 1: Three-dimensional reconstruction showing the PRPH-positive neurites (green) and the nucleus of the inner hair cell (blue) of the prosensory domain/developing organ of Corti in the lower basal turn at W12, (week 12) corresponding to Figure 5G. (M4V 3 MB)
Additional file 2: Movie 2: Three-dimensional reconstruction showing the Peripherin (PRPH)-positive neurites (green) and the nuclei of the hair cells (blue) of the developing organ of Corti in the lower basal turn at W14 (week 14), corresponding to Figure 6C. (M4V 3 MB)
Additional file 3: Movie 3: Three-dimensional reconstruction showing the Peripherin (PRPH)-positive neurites (green) and the nucleus of the inner hair cell (blue) of the developing organ of Corti in the lower basal turn at W15 (week 15), corresponding to Figure 6E. (M4V 4 MB)
Additional file 4: Movie 4: Three-dimensional reconstruction showing the Peripherin (PRPH)-positive neurites (green) and the nucleus of the inner hair cell (blue) of the developing organ of Corti in the lower basal turn at W18 (week 18), corresponding to Figure 6G. (M4V 4 MB)
Additional file 5: Movie 5: Three-dimensional reconstruction showing the Peripherin (PRPH)-positive neurites (green) and the nucleus of the inner hair cell (blue) of the developing organ of Corti in the lower basal turn at W20.3 (week 20.3), corresponding to Figure 6H. (M4V 3 MB)
Ubiquitous PRPH expression becomes restricted to type II SGNs at W18
Strikingly, by W18, the spiral ganglion was found to be largely devoid of PRPH (Figure 7D,E). Only some SGNs strongly expressed PRPH (Figure 7D). Together with the observation that PRPH-positive neurites become confined to the OHCs and their increase in a spiral orientation, this suggests the emergence of bona fide type II SGNs at W18 to W20 in humans.
Initial innervation of the cochlear duct is not conserved between mouse and human
Differentiation of the IHC at W12
Using transmission electron microscopy, Pujol and Lavigne-Rebillard previously showed that the onset of first hair cell differentiation in the human fetal cochlea starts in W12 of gestation (that is, week 10 of fetal development) . In the current study, we consistently observed epithelial reorganization in the prosensory domain concurrently with SOX9 downregulation and MYO7A expression in a single row of cells in the prosensory domain of the basal turn, indicating first (inner) hair cell differentiation at W12. However, in one cochlea from W11.4, there were identical changes in marker expression in one out of three sections of the basal turn (see Additional file 6: Figure S1), even though previous ultrastructural investigations had reported an undifferentiated poly-layered epithelium , suggesting that hair cell differentiation might already start at the end of W11.
Do SOX2 and SOX9/SOX10 differentially regulate hair cell differentiation?
In mammals and other vertebrates, it has been shown that hair cell differentiation is restricted to cells of the SOX2-positive prosensory domain . Our data are in complete agreement with these observations, as we found that the developing human cochlea at W10.4 exhibited a SOX2-positive prosensory domain in which hair cell precursors subsequently differentiated into IHCs and OHCs in a radial and longitudinal gradient. Sox2 has been shown to act on Atoh1, the key transcription factor for hair cell differentiation . Expression of Atoh1, and thereby hair cell fate commitment, is also under strict control of the Notch pathway . Interestingly, there was downregulation of SOX9 and SOX10 coincident with the moment of first hair cell commitment, which was followed several weeks later by downregulation of SOX2. The same sequence of events for SOX9 and SOX2 has been previously reported in the developing mouse cochlear duct . Together with our observations, this supports a distinct role for SOX9/SOX10 and SOX2 in hair cell fate commitment, and an evolutionarily conserved mechanism of hair cell differentiation between mice and humans. It is known from studies in other tissues that Sox9 is directly controlled by Notch activity, for example in the developing nervous system, where it is involved in glial versus neuronal cell fate , and in the developing pancreas, where Sox9 and Notch regulate endocrine versus ductal cell fate . Sox9 could possibly affect hair cell versus supporting cell fate in a similar, Notch-dependent manner. Furthermore, we observed the expression of SOX2 by supporting cells in the human cochlea up to the final stage we investigated, at W20.3. As it is currently thought that Sox2 expression in supporting cells is linked to a dormant potential of hair cell differentiation , this validates (animal) research focusing on this pathway to restore hearing. SOX2 expression in the adult human cochlea remains to be investigated.
Innervation dynamics of the cochlear duct by PRPH-positive neurites
Hair cell development progresses hand in hand with the arrival and shaping of afferent neurites into the cochlear duct epithelium . In contrast to mice, human PRPH was expressed in SGNs prior to hair cell innervation, and the dynamics in the spiral ganglion correlated perfectly with the initial steps of innervation within the developing OC in humans. We found abundant PRPH expression at W12 and W15 in SGN cell bodies and in neurites reaching both the IHCs and OHCs. At W18, PRPH expression had become limited to cells generally located at the distal end of the spiral ganglion. It is well known that type II SGNs in the adult human cochlea are also found mainly in this area . In addition, in the adult human cochlea, type II SGNs represent less than 10% of the total number of SGNs , and PRPH expression has been found to be restricted to this cell type . In relation to our observations, it can therefore be concluded that PRPH expression becomes gradually restricted to type II SGNs by W18-W20.
Onset of human hearing by W20?
Complete absence of PRPH-positive neurites projecting to IHCs was observed at W20. At this gestational stage, the IHCs were abundantly innervated by TUBB3-positive neurites. The spiral orientation of neurites projecting to OHCs was already found at W14 to W15, and was prominently present at W20. These observations are in line with adult expression patterns and orientation, providing further support for the timing of onset of human cochlear function, which is thought to take place around W20 [9–11].
The medical ethics committee of the Leiden University Medical Center approved this study (protocol 08.087), and informed consent was obtained in accordance with the WMA Declaration of Helsinki guidelines.
In total, 27 human embryonic and fetal cochleae were collected from tissue obtained by elective termination of pregnancy (by vacuum aspiration, after obstetric ultrasonography to determine gestational age in weeks and days) at various gestational stages (W10 to W20: W10, n = 4; W11, n = 1; W12, n = 4; W14, n = 4; W15, n = 2; W16, n = 1; W17, n = 4; W18, n = 4; W19, n = 2; W20, n = 1).
Time between termination and collection was kept to a minimum, ranging from one to several hours. All cochlear specimens were fixed in 4% paraformaldehyde in PBS overnight at 4°C. Cochleae obtained before W14 were dehydrated in ethanol and embedded in paraffin wax using standard procedures. Cochleae from W14 and later were decalcified for 1 to 3 weeks in 10% EDTA disodium salt (pH 7.4) (Sigma-Aldrich, St Louis, MO, USA) in distilled water at 4°C, prior to ethanol dehydration and paraffin wax embedding. Sagittal sections from E13.5 and E15.5 mouse embryos (CBA/Bl6) were a generous gift from the McLaren Laboratory (Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK). For these, E0.5 was designated as the first morning with a vaginal plug, and tissue was fixed in 4% paraformaldehyde in PBS overnight at 4°C before paraffin wax embedding.
Histology and immunofluorescence
The cochleae were sectioned (5 μm) in the sagittal plane using a RM2255 microtome (Leica Microsystems GmbH, Wetzlar, Germany). Sections were dewaxed in xylene, rehydrated in a descending ethanol series (100%, 90%, 80%, 70%), and rinsed in distilled water. Hematoxylin and eosin staining was performed by standard procedures to determine the morphology of each cochlea. For immunofluorescence, antigen retrieval was performed in 0.01 mol/l sodium citrate buffer (pH 6.0) for 12 minutes at 97°C using a microwave oven, and sections were allowed to cool to room temperature. The sections were subsequently blocked with 1% bovine serum albumin (BSA; Sigma-Aldrich) in PBS containing 0.05% Tween-20 (Promega, Leiden, the Netherlands) for 30 minutes, and incubated with primary antibodies diluted in blocking solution overnight at room temperature in a humidified chamber. The following day, the sections were incubated with secondary antibodies diluted in blocking solution for 2 hours at room temperature. Nuclei were stained with 4′,6-diamidino-2-phenylindole (DAPI; Vector Laboratories Ltd., Peterborough, UK) or TO-PRO-3 (Life Technologies, Carlsbad, CA, USA), and sections were mounted in ProLong Gold (Life Technologies). The primary antibodies used in this study were mouse anti-MYO7A (1:40; 138-1 supernatant; DSHB, Iowa City, IA, USA), rabbit anti-SOX2 (1:200; ab5603), rabbit anti-PRPH (1:200; ab1530) (both Chemicon, Temecula, CA, USA); rabbit anti-SOX9 (1:200; ab5535, Millipore Corp., Bedford, MA, USA), goat anti-SOX10 (1:50; sc-17342), mouse anti-PCNA (1:500;, ab-56) (both Santa Cruz Biotechnologies, Santa Cruz, CA, USA), and mouse anti-TUBB3 (1:200; ab78078, Abcam, Cambridge, UK). The Alexa Fluor conjugated secondary antibodies used were 488 donkey anti-mouse (1:500; A-21202), 488 donkey anti-rabbit (1:500; A-21206), 488 donkey anti-goat (1:500; A-11055), 568 donkey anti-mouse (1:500; A-10037) and 568 donkey anti-rabbit (1:500; A-10042 (all Life Technologies)). For antibody specificity controls, primary antibodies were omitted.
Image acquisition and processing
Sections stained with hematoxylin and eosin were digitized using a Pannoramic MIDI scanner (3DHISTECH, Kisvárda, Hungary) and adjusted using Pannoramic Viewer (3DHISTECH). Confocal images were taken under a Leica TCS SP5 confocal inverted microscope (Leica Microsystems), operating with the Leica Application Suite Advanced Fluorescence software (LAS AF; Leica Microsystems). Sections were scanned throughout their full depth with Z-steps of 0.5 μm (or with a sampling density according to the Nyquist rate in the case of high magnification) and Z-projections were generated. Brightness and contrast adjustments, consistent with the image manipulation policy, were performed either in LAS AF or Adobe Photoshop CS6 (Adobe Systems Inc., San José, CA, USA). Amira (version 4.1; Visage Imaging, San Diego, CA, USA) was used for 3D reconstruction of entire Z-stacks.
Organ of Corti
Inner hair cell
First row of outer hair cells
Second row of outer hair cells
Third row of outer hair cells
Outer hair cell
Proliferating cell nuclear antigen
Spiral ganglion neuron
Class III β-Tubulin.
We thank K Sprenkels, I Navarro, J Wiegant and AM van der Laan for technical support, CL Mummery for critical reading of the manuscript. We thank the Centre for Contraception, Abortion and Sexuality (CASA; Leiden, the Netherlands) for the human fetal material. Work in the laboratory of SCSL is supported by the Netherlands organization of Scientific Research (NWO) (ASPASIA 015.007.037) and Interuniversity Attraction Poles (IAP) (P7/07), and HL was supported by Stichting Het Heinsius-Houbolt Fonds.
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