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British Medical Bulletin 63:39-57 (2002)
© 2002 The British Council
Sensory organ development in the inner ear: molecular and cellular mechanisms
School of Biological Sciences, University of Sussex, Brighton, UK
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Abstract |
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Abstract
IntroductionThe molecular mechanisms underlying the specification of sensory organs in the inner ear and the development of hair and supporting cells within these organs are described. The different organs are all derived from a common pro-sensory region, and may be specified by their proximity to the boundaries between compartments – broad domains within the otocyst defined by the asymmetric expression patterns of transcription factors. Activation of Notch may specify the pro-sensory region, and lateral inhibition mediated by Notch signalling influences whether cells of common lineage in a sensory patch differentiate as either hair cells or supporting cells. The transcription factors Math1 and Brn3.1 are required for hair cell differentiation, and supporting cells express negative regulators of neurogenesis, Hes1 and Hes5. Retinoic acid and thyroid hormone influence early aspects and timing of hair cell differentiation, respectively. Development of the hair cell's mechanosensory hair bundle involves interactions between the cytoskeleton, cell-surface adhesion molecules, receptors and associated extracellular matrix.
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Introduction |
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There are six distinct sensory organs in the mammalian inner ear: the three cristae of the semicircular canals, the two maculae of the saccule and utricle, and the organ of Corti of the cochlea (Fig. 1). The cristae and the maculae are vestibular organs that respond to angular and linear acceleration, respectively. The organ of Corti is the organ of hearing. These three types of organ differ in their function, and in the fine details of their cellular architecture, but they all conform to the same basic plan. They are relatively simple epithelia composed of two basic cell types, the sensory hair cells and their surrounding, non-sensory supporting cells. These epithelia lie upon a sheet of extracellular matrix, a basal lamina, and also have a prominent extracellular structure, a cupula, an otoconial membrane or a tectorial membrane, associated with their apical surface. The supporting cells sit on the basal lamina, and their lateral membranes surround the hair cells, projecting up to the surface of the epithelium. The hair cells do not contact the basal lamina, and they are isolated from one another by the supporting cells. At the apical surface of the epithelium, the supporting cell processes form tight and adherens junctions with each other and with the hair cells. The hair cells have a highly specialized bundle of modified microvilli on their apical surface, a hair bundle, and it is this feature that enables them to detect mechanical stimuli and transduce them into electrical signals.
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These sensory organs of the inner ear are all derived during development from the wall of the otocyst, a hollow, pear-shaped structure that forms, just after neural tube closure, from a thickening of the head ectoderm that lies adjacent to the rhombencephalon and is known as the otic placode. The neurones that innervate the hair cells in each organ of the ear are also derived from the otocyst, by a process of delamination, prior to the formation the sensory organs. Although these neurones become critically dependent on trophic support from the hair cells1,2, there is little evidence that they influence the development of hair and supporting cells. In this brief review, we will focus specifically on the sequence of molecular and cellular events that leads to the differentiation of hair and supporting cells within these epithelial organs, rather than the process of synaptogenesis. We will describe the origin of the different sensory organs, the lineage relationships of hair and supporting cells, and how the two cell types come to adopt different fates. The roles of retinoic acid and thyroid hormone will be discussed, and recent evidence indicating that a complex interplay between the cytoskeleton, components of the hair cell surface and the associated extracellular matrix controls the process of hair bundle development will be reviewed.
Much of our understanding about the development of the inner ear comes from a number of different systems, and not just from the experiments done with mammalian species. Studies on the developing chick inner ear, and more recently that of the zebrafish, provide considerable information on basic mechanisms and principles that are likely to be applicable to the process of hair and supporting cell development in both mice and humans. For certain aspects, detailed data are only available for the chick and, when necessary, these will be used to illustrate how the sensory patches in the inner ear are formed.
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Generation and specification of sensory organs |
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Histological studies3 originally suggested that the different sensory organs of the chick inner ear are all derived from a single patch of cells in the ventromedial wall of the otocyst. Molecular studies have recently revived support for this suggestion, and have revealed that there is a pro-sensory area in the ventromedial region of the otocyst that can be defined by the expression patterns of Serrate14, Lunatic fringe4 and BEN5. Serrate1 (known as Jagged1 in mammals) is a transmembrane ligand for Notch, a membrane receptor that is involved in many aspects of development6. Lunatic fringe is a protein that modulates interaction between Notch and its ligands7. BEN is a cell–cell adhesion molecule of the Ig superfamily8. Notch is widely expressed throughout the otocyst9, and Serrate1 may serve to maintain a high level of Notch activation within the pro-sensory patch, endowing this region with the capacity to form sensory organs, and preventing the premature differentiation of hair cells10. The role of Lunatic fringe in the pro-sensory patch is uncertain. Lfng-/- mice do not have any inner ear abnormalities11, and it may only act as a weak inhibitor of Notch signalling10. As a cell–cell adhesion molecule, BEN may serve to stop the cells of the pro-sensory patch from mixing with cells in other regions of the otocyst, i.e. those that are destined to become non-sensory parts of the ear5. Although these studies provide evidence for the existence of a common pro-sensory patch and reveal molecular constituents with potential roles, it is not yet known what signals determine the formation of this region, or from where these signals emanate.
A boundary model has been proposed to account for how the different sensory organs of the inner ear are specified12. This model postulates that the different sensory organs of the inner ear form at, or in proximity to, the boundaries between a small number of different compartments. These compartments are defined by the asymmetric expression patterns of a few genes and may, for example, correspond to the ventral and dorsal halves, or the anterior and posterior segments of the otocyst. Genes for transcription factors such as Pax2, Dlx5, Otx1 and Hmx3 are expressed in such broad domains in the otocyst, and data from knockout mice are consistent with the boundary model (see Brigande et al13 and Cantos et al14 for reviews). For example, anterior and posterior cristae along with their associated canals are missing in Dlx5-/- mice15. Also Pax2-/- mice fail to form a cochlear duct16. Compartment boundary intersection points may, therefore, define where a sensory organ forms within the ventromedial pro-sensory patch, and whether it becomes a crista, a macula, or a hearing organ.
The expression of BMP4 in spatially discrete regions within the ventromedial pro-sensory patch marks the first appearance of individual sensory organs17,18. BMP4 is a member of the TGF-ß family of secreted growth factors and, in the chick otocyst, BMP4 is expressed in all of the sensory organs as they first emerge17. However, BMP4 is not a good marker for every sensory organ in the mouse otocyst18, and it is only expressed in some of the organs in the zebrafish ear19. Although BMP4 could autonomously regulate the development of hair and supporting cells within the organs within which it is expressed, it may actually play a major role in controlling the development of the accessory structures that form adjacent to the sensory patches. For example, the BMP4 antagonist Noggin severely disrupts semicircular canal formation but has comparatively little effect on the development and differentiation of hair cells20,21. FGF10 is also expressed by the presumptive sensory epithelia of the mouse otocyst, and it too may operate in a paracrine fashion, signalling through the IIIb isoform of FGFR-2 to control the development of adjacent non-sensory tissues22. A number of other genes are also expressed in sensory patches at the very early stages of their development. These include BMP5 and BMP723, p75NGFR24,25, Msx117, NT318,24, bmp2b19, and MsxC19,26. Some of these, like MsxC, are only expressed in certain sensory patches, and may specify the type of organ that develops.
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Lineage and birth of hair and supporting cells |
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Hair and supporting cells in the mammalian inner ear are born over a brief period of development after the sensory patches have been specified27,28. The cells then differentiate and remain mitotically inactive. In the cochlea of the mouse, the cyclin-dependent kinase inhibitor, p27Kip1, is expressed by cells of the organ of Corti as soon as they withdraw from the cell cycle29,30. The pattern of p27Kip1 expression precisely delineates the region of the cochlear duct within which the hair and supporting cells of the organ of Corti will differentiate. The expression of p27Kip1 is down-regulated in hair cells as they begin overt cytodifferentiation, but in supporting cells it persists into adulthood29. In p27Kip1-/- mice, cell proliferation within the organ of Corti continues, and an excess of hair and supporting cells is found29,31. These data indicate p27Kip1 negatively regulates cell proliferation in the organ of Corti. However, other molecules must also control this process as many hair and supporting cells do leave the cell cycle and differentiate in the cochleae of p27Kip1 knockout mice.
In the hearing organs of both mammals27 and birds32, hair and supporting cells at any one place within the structure are born simultaneously, suggesting they may share a common lineage. Retroviral tracing studies in the chick auditory organ have provided firm experimental evidence for this suggestion33,34. Furthermore, it has been shown that the potential to become either a hair or a supporting cell is retained by a progenitor cell until it has passed through its final mitotic division, as two-cell clones were found that contained either two supporting cells, two hair cells or both cell types33.
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The differentiation of hair and supporting cells |
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The decision to become either a hair cell or a supporting cell most probably involves lateral inhibition35,36, a process by which cells of common origin adopt different fates. Lateral inhibition is usually mediated by Notch signalling, and a number of studies have now shown that the products of the neurogenic genes of the Notch signalling pathway play a key role in mediating the differentiation of hair and supporting cells in the inner ear9,10,37–45. The expression patterns of these genes in the ear, and the phenotypes of the different mutants that have been examined, are summarised in Table 1. In addition, a number of transcription factors have been shown to be involved in the process of hair and supporting-cell differentiation46–54, some of which may directly interact with the Notch signalling pathway. These are also listed in Table 1. The expression patterns of both the neurogenic genes and the transcription factors, the consequences of experimentally manipulating their expression, are now described and discussed in detail.
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Math1 Math1, a mouse homologue of the Drosophila proneural gene atonal, encodes a basic, helix-loop-helix (bHLH) transcription factor. It is expressed in the primordium of the organ of Corti after the cells in this region have withdrawn from the cell cycle and have begun to express p27Kip1, but before hair cells have started to express myosin VIIa, a marker of overt differentiation30. Math1 is initially expressed by thin bands of cells that span the entire thickness of the epithelium, and expression becomes restricted to hair cells located at the lumenal surface of the epithelium as they differentiate30,54. These thin bands of Math1-expressing cells that initially span the thickness of the epithelium may be bi-potential progenitor cells54. Alternatively, they may be vertical stacks of hair cells that subsequently undergo movement within the thickness of the epithelium and spread out along the longitudinal axis of the cochlea as it elongates30.
Hair cells are absent from the inner ears of Math1-/- mice by birth50, and the ectopic expression of Math1 in the non-sensory cells of the greater epithelial ridge that lie adjacent to the organ of Corti results in the formation of supernumerary hair cells51. These results indicate that Math1 is both ‘necessary and sufficient’ for hair cell differentiation30. Early markers of overt hair cell differentiation, myosin VI and calretinin, are never expressed during inner ear development in Math1-/- mice50. The sensory epithelia are thinner and non-stratified, but have an overlying extracellular matrix suggesting the supporting cells may have differentiated. An apparent overcrowding of supporting-cell nuclei and a failure to observe apoptosis in the sensory epithelia of Math1-/- mice was originally interpreted as indicating that a fate switch had occurred, leading to an overproduction of supporting cells50. However, apoptotic cells have recently been reported in the organ of Corti of Math1-/- mice, so the hair cells may be produced, fail to express any known markers of differentiation, and then die30. Sensory epithelia, albeit eventually devoid of hair cells, do form in Math1-/- mice, so it is unlikely that Math1 is acting as a true proneural gene like its invertebrate homologue atonal50. A proneural gene required for sensory organ specification in the inner ear has, therefore, yet to be discovered.
Delta1, Jagged2 and Notch1 Delta1 and Jagged2 (known as Serrate2 in chick) are expressed by hair cells in the mouse cochlea approximately 1 day after the onset of Math1 expression38,40. In Jagged2 null mutant mice, there is an increase in the linear density of inner and outer hair cells in the cochlea, with a nearly complete duplication of the normal, single row of inner hair cells, and many stretches where there are four instead of three rows of outer hair cells40. Delta mutants have not been studied in the mouse, but a dominant negative allele of the zebrafish deltaA gene, deltaAdx2, results in a 5–6-fold increase in hair cell numbers in the inner ear, and a loss of most of the supporting cells41. Notch expression is initially widely distributed throughout the inner ear epithelium and the sensory patches, and becomes restricted to the supporting-cell layer as the hair cells differentiate9,39,40,42,43. Notch1-/- mice are early embryonic lethals, but in heterozygotes with presumably reduced levels of Notch1, a significant increase is observed in the numbers of regions along the cochlea where there are four instead of three rows of outer hair cells11. Treating rat cochlear cultures with antisense Notch oligonucleotides causes the production of extra rows of both inner and outer hair cells43. The expression of Delta1 and Jagged2 in hair cells, and the overproduction of hair cells seen in corresponding mutants and with antisense oligonucleotides to Notch1, all indicate that hair cells use Notch signalling to inhibit laterally their neighbouring cells and thereby prevent them from adopting the same fate.
Serrate1/Jagged1 Serrate1/Jagged1 is expressed throughout the pro-sensory patch initially4,9,38, but becomes progressively restricted to the supporting cells as they differentiate38,39. The expression of Serrate1/Jagged1 by supporting cells may not appear to be consistent with the idea that hair cells inhibit their neighbours. However, there is evidence from the chick that hair cells express Numb, a protein that blocks Notch signalling10. These hair cells would, therefore, be deaf to signals delivered by Serrate1 from adjacent supporting cells. Furthermore, there is also evidence from the chick inner ear that the expression of Serrate 1 in supporting cells is positively regulated by Notch signalling via lateral induction10. This would serve to increase the level of Notch activation amongst the supporting cells, and ensure that they do not differentiate as hair cells. The overproduction of hair cells in late embryonic rat cochlear cultures caused by Jagged1 antisense oligonucleotides43 is consistent with this, as reduced Notch activation should lead to an excess of hair cells. However, in mouse mutants44,45, Jagged1 mutations that are assumed to be dominant negative lead to the complete loss of some sensory organs (cristae) and only perturb hair cell patterning in others (cochlea). This could be because Serrate1/Jagged1 has an early role in specifying sensory patches and/or preventing their premature differentiation, and a later role in regulating the development of hair and supporting cells within the patch44. Whilst this may partially explain why the mutations, which are effective throughout development, and antisense treatment, which has only been applied at relatively late developmental stages, have different effects, it does not explain why the different organs in the ears of Jagged1 mutant mice respond differently to the same mutation. However, the loss of cristae may occur secondarily to the truncation of the canals, which in turn may be due to diminished BMP4 signalling from the sensory patch resulting from reduced Notch activation.
The expression patterns of the neurogenic genes described above and the phenotypes of the different mutants that have been examined are generally in accordance with the theory that hair cells laterally inhibit their neighbours and force them to become supporting cells. However, the situation is clearly more complex than originally envisioned35,36. Although a stochastic fluctuation in Notch signalling in a field of cells initially expressing uniform levels of Notch and Delta can theoretically lead, as a result of negative feedback, to the production of regular mosaics of hair and supporting cells55,56, Delta1 is not uniformly expressed38, there are two other Notch ligands operating in the ear, and the signalling pathway can be modulated at many levels, making the simple scenario, although attractive, less likely. Furthermore, an active re-arrangement of hair and supporting cells relative to one another may contribute to the formation of a precise cellular mosaic, and refine the imperfect patterns that are initially observed during the early stages of development57, indicating that lateral inhibition with feedback is not the only mechanism contributing to pattern formation in the sensory epithelia. The expression patterns for the neurogenic genes and the experimental findings described above are largely consistent with a system of regulatory interactions (see Fig. 2) recently proposed by Lewis and colleagues10.
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Hes1 and Hes5 Hes1 and Hes5, mammalian homologues of the Drosophila hairy and enhancer of Split genes, are expressed in patterns that are both complementary and overlapping in the developing cochlea and utricle of the mammal52,53. The products of these genes act as negative regulators of neurogenesis in vertebrates58. Expression of Hes5 is first observed in the supporting cells of the organ of Corti after the expression of Math1 has begun in differentiating hair cells, and probably slightly after the onset of expression of Delta1 and Jagged254. The expression of Hes5 may be positively regulated by Notch activation as it is much reduced in the supporting cells (Deiter's cells) of Jag2-/- mice54. Additional inner hair cells are observed in Hes1-/- mutant mice, and additional outer hair cells are observed in Hes5-/- mutants52,53, generally consistent with the expression patterns of these genes and their proposed role as negative regulators of hair cell differentiation. Hes1 may directly antagonize the activity of Math1, as co-transfecting cells in cochlear cultures with Hes1 and Math1, blocks the effects of ectopic Math1 expression52, reducing the production of supernumerary hair cells.
Brn3.1 and GATA3 Brn3.1 (also called Brn3c) is a POU domain transcription factor that is specifically expressed by hair cells within the adult mouse inner ear46,47. Brn3.1 is expressed by postmitotic hair cells at approximately the same time as Jagged2 and Delta1, 1 day before the hair cell markers myosin VI and myosin VIIa48. In Brn3.1-/- mice, hair cells are generated and express myosin VI, myosin VIIa and calretinin, but they never develop sensory hair bundles and are lost from the inner ear by P1446,47. The ectopic overexpression of Brn3.1 does not lead to the production of hair cells51, indicating Brn3.1 is only required for the later aspects of hair cell differentiation. GATA3 is another transcription factor that may be involved in cell differentiation within the sensory patches. All epithelial cells in the dorsal wall of the cochlear duct express GATA3, and its expression selectively decreases in both hair and supporting cells as they differentiate, indicating it may act as a negative regulator of hair and supporting-cell differentiation49.
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Roles of thyroid hormone and retinoic acid in hair cell differentiation |
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Nuclear receptors for thyroid hormone and retinoic acid are expressed in the developing sensory epithelia of the inner ear and their respective ligands are known to play roles in hair cell development (see Raz and Kelley59 for recent review). Retinoic acid is produced by the embryonic, but not adult, organ of Corti, and treating cochlear cultures from early, but not late, embryonic stages of development with retinoic acid leads to the production of extra rows of inner and outer hair cells60. The RAR
/RXR heterodimer is the most likely hair cell receptor for retinoic acid, and application of the RAR antagonist Ro-41-5253 to cochlear cultures leads to a reduction in the number of hair cells that eventually develop61. However Ro-41-5253 does not block the initial differentiation of hair cells, as judged by the expression of Brn3.1 and myosin VI61, so it has been suggested that retinoic acid induces certain early aspects of hair cell differentiation rather than determining the size of the pro-sensory cell population61.
The three functional thyroid hormone receptors, TR1, TRß1 and TRß2, and the non-ligand binding TR2 are expressed in the sensory epithelia of the inner ear from early stages, with the expression of TRß1 and TRß2 being restricted to the cochlear epithelium62. Chemically induced hypothyroidism results in a delay in the maturation of most elements in the organ of Corti, and the same effect is observed in transgenic mice that lack all known thyroid hormone receptors63. TRß is essential for the development of hearing64 and in Thrb-/- mice there is a delay in the onset of the fast potassium conductance (IK,f) in inner hair cells, but the onset of outer hair cell motility is unaffected65. Although IK,f is eventually expressed by inner hair cells in Thrb-/- mice, hearing does not recover, possibly due to a permanent impairment of the tectorial membrane63. In Thra-/-/Thrb-/- compound null mutant mice both the onset of IK,f and outer hair cell motility is delayed63, and a recent study has shown that the gene encoding prestin, the outer hair cell motor66, is regulated by thyroid hormone67.
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Development of the sensory hair bundle |
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The sensory hair bundle, a precisely determined array of actin-filled stereocilia located on the hair cell's apical surface, is a distinguishing characteristic of the hair cell and is essential for the process of mechanotransduction. The development of the hair bundle is a complex process and, for the auditory organ of the avian inner ear, the morphological details have been described thoroughly (see Tilney and Tilney68 for review). For the mammal, this process has been best characterized in the mouse vestibular system69,70, and the cochlea of the hamster71 and the rat72. For the mouse cochlea, information is somewhat limited.
Although there are some inter-species and inter-organ differences, the general features of the process of hair bundle development can be described as follows. First, small stereocilia sprout up over the entire apical surface of the hair cell, clustering around a centrally located kinocilium to form a short bundle of uniform height. Second, the kinocilium migrates to one side of the cell and the stereocilia nearest the kinocilium begin to elongate and generate the staircase pattern in which adjacent rows of stereocilia become arranged in increasing height with the tallest row lying next to the now eccentrically placed kinocilium. The position of the kinocilium, therefore, defines the planar polarity of the hair cell and its bundle. Third, rootlets project down from the stereocilia, anchoring them into the cuticular plate, and the excess supernumerary stereocilia that have not been incorporated into the ranked rows of the bundle are re-absorbed. Finally, the stereocilia within the bundle grow to their final width and height, and the bundle achieves its mature shape and form. In the chick auditory organ, increases in the width and height of stereocilia occur over different time periods68, whereas in mammals both processes, thickening and lengthening, occur concurrently71. Also, differences in bundle height in the avian hearing organ may be governed by regulating the period over which the growth of stereocilia occurs at a constant rate68, whereas in the mammalian cochlea they may be generated by differences in growth rate71.
Surprisingly little is known about the molecular basis of hair bundle development in any species. Clearly, it will involve molecules and pathways that direct the assembly of the actin cytoskeleton, like the Rho-GTPases along with their upstream effectors and their downstream targets, and two recent reviews have suggested how this may be accomplished73,74. However, thus far, studies on mouse mutants and human deafness genes have provided the greatest insight into the molecular processes that may be involved in hair bundle development.
Mice with mutations in the genes that underlie deaf-blindness in three of the genetic forms of the human Usher type I syndrome, USHIB, USHID and USHIF, exhibit defects in hair-bundle development. These genes encode the unconventional myosin, myosin VIIa (shaker-1 mouse75), and two cell adhesion molecules, cadherin 23 (waltzer mouse76) and protocadherin 15 (Ames waltzer mouse77). Bundles with ranked rows of stereocilia form in all three mouse mutants, but by the early stages of postnatal development, they show varying degrees of disruption and are often fragmented into several smaller units75–77, suggesting there may be defects in the mechanisms of inter-stereociliary adhesion. The USHIC gene encodes a PDZ domain protein that is present in stereocilia and could act as an interface between the cytoskeleton and the plasma membrane78, although it is not yet known how mutations in this gene affect hair bundle development. Interactions between the actin cytoskeleton, unconventional myosins, PDZ domain proteins and cell-surface adhesion molecules may, therefore, play a pivotal role in the development of hair bundle integrity. Mutations in two other unconventional myosins, cause non-syndromic human hereditary deafness and cause defects in hair bundle development in the corresponding mouse mutants. Defects in myosin VI (Snell's waltzer mouse79) lead to the fusion of stereocilia and the formation of giant bundles in the early postnatal period80. Myosin VI is unusual as it is a minus-end directed actin motor81, unlike most other myosins that move towards the plus, or barbed, ends of actin filaments. It is not found in stereocilia and it has been proposed80 that it tethers the apical membrane around the base of each stereocilium to the rootlet or the cuticular plate, thereby stabilising the stereocilium. Defects in myosin XV (shaker-2 mouse82) lead to the production of hair bundles that are abnormally short, although of normal shape and with height-ranked rows of stereocilia. Abnormally long actin filament bundles, cytocauds, are found in these hair cells that project many microns from the base of the cell83, suggesting a mis-regulated deployment of a limited supply of actin monomers may account for the reduction in bundle height observed.
Integrins are cell surface receptors for extracellular matrix molecules and a recent study84 has shown that the 8 integrin subunit specifically localizes to the apical pole of developing utricular hair cells along with focal adhesion kinase (FAK), and that the extracellular matrix molecules fibronectin and collagen type IV are associated with the apical surface of the developing epithelium. Transgenic inactivation of the 8 integrin subunit leads to the malformation of a subset of utricular hair bundles, a loss of FAK from the apical pole of the hair cell and a disappearance of fibronectin from the apical epithelial surface. The growth of sensory hair bundles may, therefore, involve reciprocal interactions between hair bundle receptors and matrix molecules associated with the apical surface of the sensory epithelia.
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Conclusions and key points for clinicians |
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The evidence reviewed suggests the following sequence of molecular events occurs during the differentiation of sensory organs in the inner ear (Fig. 3). The different sensory organs all originate from a single common patch in the otocyst that can be defined by the expression of Serrate1, Lunatic fringe, and BEN. Notch is present throughout the otocyst, and is maintained in an activated state within the pro-sensory patch by Serrate1. Notch activation can also laterally induce Serrate1/Jagged1, re-inforcing the expression of Serrate1/Jagged1 in cells with activated Notch. Notch activation may make the patch sensory-competent, and prevent the premature differentiation of hair cells. Discrete regions within this pro-sensory patch then become specified to form different types of organs, cristae, maculae or a cochlea, possibly by virtue of their position relative to compartment boundaries within the inner ear. Hair and supporting cells share a common lineage, and express p27Kip1, a cyclin-dependent kinase inhibitor, as soon as they withdraw from the cell cycle. Once postmitotic, the hair cells express Math1, followed by Delta1, Jagged2/Serrate2 and Brn3.1 At some stage during this process, possibly during the final round of cell division, the presumptive hair cells acquire Numb, thereby rendering them deaf to Jagged1/Serrate1 signalling from the supporting cells. This decreases Notch activation in the presumptive hair cells, further promoting their differentiation along the hair cell pathway. Delta1 and Jagged2/Serrate2 signalling from hair cells increases the levels of Notch activation in supporting cells, preventing them from expressing Delta1 and Jagged2/Serrate2, and inhibiting hair cell differentiation, probably by positively regulating the expression of Hes1/5. Levels of Notch activation, therefore, determine whether a cell becomes a hair cell (low levels) or a supporting cell (high levels); intermediate levels may maintain cells as pro-sensory progenitors. Retinoic acid may control an early event in the differentiation of hair cells, but probably does not determine the size of the pro-sensory cell population. Brn3.1 is required for the later stages of hair cell differentiation, including the appearance of a sensory hair bundle, the full and complete development of which may involve interactions between the cytoskeleton, cell adhesion molecules, cell-surface receptors and surface associated extracellular matrix. Finally, thyroid hormone controls the timing of certain aspects of hair cell differentiation, including the expression of ion channels and, in cochlear outer hair cells, the motor protein, prestin.
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Acknowledgements |
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Jane Bryant is an MRC postgraduate student. Richard Goodyear and Guy Richardson are supported with funds from The Wellcome Trust. The authors would like to thank Stuart Johnson for his help with figure preparation.
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Footnotes |
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Correspondence to: Dr Guy P Richardson, School of Biological Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK
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References |
|---|
- Rubel EW, Fritzsch B. Auditory system development: primary auditory neurons and their targets. Annu Rev Neurosci 2002; 25: 51–101[Medline]
- Fritzsch B, Pirvola U, Ylikowski J. Making and breaking the innervation of the inner ear: neurotrophic support during ear development and its clinical implications. Cell Tissue Res 1999; 295: 369–82[Web of Science][Medline]
- Knowlton VY. Correlation of the development of membranous and bony labyrinths, acoustic ganglia, nerves, and brain centers of chick embryos. J Morphol 1967; 121: 179–208
- Cole LK, Le Roux I, Nunes B, Laufer E, Lewis J, Wu DK. Sensory organ generation in the chick inner ear: contributions of bone morphogenetic protein 4, Serrate1, and Lunatic Fringe. J Comp Neurol 2000; 424: 509–20[Web of Science][Medline]
- Goodyear RJ, Kwan T, Oh S-H, Raphael Y, Richardson GP. The cell adhesion molecule BEN defines a prosensory patch in the developing avian otocyst. J Comp Neurol 2001; 434: 275–88[Web of Science][Medline]
- Bray S. Notch signalling in Drosophila: three ways to use a pathway. Semin Cell Dev Biol 1998; 9: 591–7[Web of Science][Medline]
- Moloney DJ, Panin VM, Johnston SH et al. Fringe is a glycosyl transferase that modifies Notch. Nature 2000; 406: 369–75[Medline]
- Pourquié O, Corbel C, Le Caer J-P, Rossier J, Le Douarin NM. BEN, a surface glycoprotein of the immunoglobulin superfamily, is expressed in a variety of developing systems. Proc Natl Acad Sci USA 1992; 89: 5261–5
[Abstract/Free Full Text] - Adam J, Myat A, Le Roux I et al. Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development. Development 1998; 125: 4645–54[Abstract]
- Eddison M, Le Roux I, Lewis J. Notch signalling in the development of the inner ear: lessons from Drosophila. Proc Natl Acad Sci USA 2000; 97: 1692–9
- Zhang N, Martin GV, Kelley MW, Gridley T. A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea. Curr Biol 2000; 10: 659–62[Web of Science][Medline]
- Fekete DM. Cell fate specification in the inner ear. Curr Opin Neurobiol 1996; 6: 533–41[Web of Science][Medline]
- Brigande JV, Kiernan AE, Gao X, Iten LE, Fekete DM. Molecular genetics of pattern formation in the inner ear: Do compartment boundaries play a role. Proc Natl Acad Sci USA 2000; 97: 11700–6
[Abstract/Free Full Text] - Cantos R, Cole LK, Acampora D, Simeone A, Wu DK. Patterning of the mammalian cochlea. Proc Natl Acad Sci USA 2000; 97: 11707–13
[Abstract/Free Full Text] - Acampora D, Merlo GR, Paleari L et al. Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. Development 1999; 126: 3795–809[Abstract]
- Torres M, Gomez-Pardo E, Gruss P. Pax2 contributes to inner ear patterning and optic nerve trajectory. Development 1996; 122: 3381–91[Abstract]
- Wu DK, Oh S-H. Sensory organ generation in the chick inner ear. J Neurosci 1996; 16: 6454–62
[Abstract/Free Full Text] - Morsli H, Choo D, Ryan A, Johnson R, Wu DK. Development of the mouse inner ear and origin of its sensory organs. J Neurosci 1998; 18: 3327–35
[Abstract/Free Full Text] - Mowbray C, Hammerschmidt M, Whitfield TT. Expression of BMP signalling pathway members in the developing zebrafish inner ear and lateral line. Mech Dev 2001; 108: 179–84[Web of Science][Medline]
- Chang W, Numes FD, De Jesus-Escobar JM, Harland R, Wu DK. Ectopic noggin blocks sensory and nonsensory organ morphogenesis in the chicken inner ear. Dev Biol 1999; 216: 369–81[Web of Science][Medline]
- Gerlach LM, Hutson MR, Germiller JA, Nguyen-Luu D, Victor JC, Barald KF. Addition of the BMP4 antagonist, noggin, disrupts avian inner ear development. Development 2000; 127: 45–54[Abstract]
- Pirvola U, Spencer-Dene B, Xing-Qun L et al. FGF/FGFR-2(IIIb) signalling is essential for inner ear morphogenesis. J Neurosci 2000; 20: 6125–34
[Abstract/Free Full Text] - Oh S-H, Johnson R, Wu DK. Differential expression of bone morphogenetic proteins in the developing vestibular and auditory sensory organs. J Neurosci 1996; 16: 6463–75
[Abstract/Free Full Text] - Von Bartheld CS, Patterson SL, Heuer JG, Wheeler EF, Bothwell M, Rubel EW. Expression of nerve growth factor (NGF) receptors in the developing inner ear of chick and rat. Development 1991; 113: 455–70[Abstract]
- Pirvola U, Arumäe U, Moshnyakov M, Palgi J, Saarma M, Ylikoski J. Coordinated expression and function of neurotrophins and their receptors in the rat inner ear during target innervation. Hear Res 1994; 75: 131–44[Web of Science][Medline]
- Ekker M, Akimenko MA, Bremiller R, Westerfield M. Regional expression of three homeobox transcripts in the inner ear of zebrafish embryos. Neuron 1992; 9: 27–35[Web of Science][Medline]
- Ruben RJ. Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. Acta Otolaryngol Suppl 1967; 220: 1–44
- Sans A, Chat M. Analysis of temporal and spatial patterns of rat vestibular hair cell differentiation by tritiated thymidine radioautography. J Comp Neurol 1982; 206: 1–8[Web of Science][Medline]
- Chen P, Segil N. p27Kip1 links cell proliferation to morphogenesis in the developing organ of Corti. Development 1999; 126: 1581–90[Abstract]
- Chen P, Johnson JE, Zoghbi HY, Segil N. The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 2002; 129: 2495–505[Medline]
- Lowenheim H, Furness DN, Kil J et al. Gene disruption of p27Kip1 allows cell proliferation in the postnatal and adult organ of Corti. Proc Natl Acad Sci USA 1999; 96: 4084–8
[Abstract/Free Full Text] - Katayama A, Corwin JT. Cell production in the chicken cochlea. J Comp Neurol 1989; 81: 129–35
- Fekete DM, Muthukumar S, Karagogeos D. Hair and supporting cells share a common progenitor in the avian inner ear. J Neurosci 1998; 18: 7811–21
[Abstract/Free Full Text] - Lang H, Fekete DM. Lineage analysis in the chicken inner ear shows differences in clonal dispersion for epithelial, neuronal, and mesenchymal cells. Dev Biol 2001; 234: 120–37[Web of Science][Medline]
- Lewis J. Rules for the production of sensory hair cells. Ciba Found Symp 1991; 160: 25–39[Medline]
- Corwin JT, Jones JE, Katayama A, Kelley MW, Warchol ME. Hair cell regeneration: the identities of progenitor cells, potential triggers and instructive cues. Ciba Found Symp 1991; 160: 103–20[Medline]
- Haddon C, Jiang Y-J, Smithers L, Lewis J. Delta-Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant. Development 1998; 125: 4637–44[Abstract]
- Morrison A, Hodgetts C, Gossler A, Hrabé de Angelis M, Lewis J. Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear. Mech Dev 1999 84: 169–72[Web of Science][Medline]
- Stone JS, Rubel EW. Delta1 expression during avian hair cell regeneration. Development 1999; 126: 961–73[Abstract]
- Lanford PJ, Lan Y, Jiang R et al. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 1999; 21: 289–92[Web of Science][Medline]
- Riley B, Chiang M-Y, Farmer L, Heck R. The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1 Development 1999; 126: 5669–78[Abstract]
- Shailam R, Lanford PJ, Dolinsky CM, Norton C, Gridley T, Kelley MW. Expression of proneural and neurogenic genes in the embryonic mammalian vestibular system. J Neurocytol 1999; 28: 809–19[Web of Science][Medline]
- Zine A, Van de Water TR, de Ribaupierre F. Notch signalling regulates the pattern of auditory hair cell differentiation in mammals. Development 2000; 127: 3373–83[Abstract]
- Kiernan AE, Ahituv N, Fuchs H et al. The Notch ligand Jagged1 is required for inner ear sensory development. Proc Natl Acad Sci USA 2001; 98: 3873–8
[Abstract/Free Full Text] - Tsai H, Hardisty RE, Rhodes C et al. The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti. Hum Mol Genet 2001; 10: 507–12
[Abstract/Free Full Text] - Erkman L, McEvilly RJ, Luo L et al. Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 1996; 381: 603–6[Medline]
- Xiang M, Gan L, Li D et al. Essential role of POU-domain transcription factor Brn-3c in auditory and vestibular hair cell development. Proc Natl Acad Sci USA 1997; 94: 9445–50
[Abstract/Free Full Text] - Xiang M, Gao W-Q, Hasson T, Shin JJ. Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. Development 1998; 125: 3935–46[Abstract]
- Rivolta MN, Holley MC. GATA3 is downregulated during hair cell differentiation in the mouse cochlea. J Neurocytol 1998; 27: 637–47[Web of Science][Medline]
- Bermingham NA, Hassan BA, Price SD et al. Math1: an essential gene for the generation of inner ear hair cells. Science 1999; 284: 1837–41
[Abstract/Free Full Text] - Zheng JL, Gao W-Q. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci 2000; 3: 580–6[Web of Science][Medline]
- Xheng JL, Shou J, Guillemot F, Kageyama F, Gao W-Q. Hes1 is a negative regulator of inner ear hair cell differentiation. Development 2000; 127: 4551–60[Abstract]
- Zine A, Aubert A, Qiu J et al. Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. J Neurosci 2001; 21: 4712–20
[Abstract/Free Full Text] - Lanford PJ, Shailam R, Norton CR, Gridley T, Kelley MW. Expression of Math1 and Hes5 in the cochlea of wild type and Jag2 mutant mice. J Assoc Res Otolaryngol 2000; 1: 161–71[Medline]
- Collier JR, Monk NA, Maini PK, Lewis JA. Pattern formation by lateral inhibition: a mathematical model of Delta-Notch intercellular signalling. J Theor Biol 1996; 183: 429–46[Web of Science][Medline]
- Pickles JO, van Heumen WRA. Lateral interactions account for the pattern of the hair cell array in the chick basilar papilla. Hear Res 2000; 145: 65–74[Web of Science][Medline]
- Goodyear R, Richardson G. Pattern formation in the basilar papilla: evidence for cell rearrangement. J Neurosci 1997; 17: 6289–301
[Abstract/Free Full Text] - Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R. Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 1999; 18: 2196–207[Web of Science][Medline]
- Raz Y, Kelley MW. Effects of retinoid and thyroid receptors during development of the inner ear. Semin Cell Dev Biol 1997; 8: 257–64[Web of Science][Medline]
- Kelley MW, Xu XM, Wagner MA, Warchol ME, Corwin JT. The developing organ of Corti contains retinoic acid and forms supernumerary hair cells in response to exogenous retinoic acid in culture. Development 1993; 119: 1041–53[Abstract]
- Raz Y, Kelley MW. Retinoic acid signalling is necessary for the development of the organ of Corti. Dev Biol 1999; 213: 180–93[Web of Science][Medline]
- Bradley DJ, Towle HC, Young III WS. and ß thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo. Proc Natl Acad Sci USA 1994; 91: 439–43
[Abstract/Free Full Text] - Rüsch A, Ng L, Goodyear R et al. Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors. J Neurosci 2001; 21: 9792–800
[Abstract/Free Full Text] - Forrest D, Erway LC, Ng L, Altschuler R, Curran T. Thyroid hormone receptor ß is essential for development of auditory function. Nat Genet 1996; 13: 354–7[Web of Science][Medline]
- Rüsch A, Erway LC, Oliver D, Vennstrom B, Forrest D. Thyroid hormone receptor ß-dependent expression of a potassium conductance in inner hair cells at the onset of hearing. Proc Natl Acad Sci USA 1998; 95: 15758–62
[Abstract/Free Full Text] - Zheng J, Shen W, He DZZ, Long KB, Madison LD, Dallos P. Prestin is the motor protein of cochlear hair outer hair cells. Nature 2000; 405: 149–55[Medline]
- Weber T, Zimmerman U, Winter H et al. Thyroid hormone is a critical determinant for the regulation of the cochlear motor protein prestin. Proc Natl Acad Sci USA 2002; 99: 2901–6
[Abstract/Free Full Text] - Tilney LG, Tilney MS. Actin filaments, stereocilia, and hair cells: how cells count and measure. Annu Rev Cell Biol 1992; 8: 257–74[Web of Science][Medline]
- Mbiene J-P, Sans A. Differentiation and maturation of the sensory hair bundles in the fetal and postnatal vestibular receptors of the mouse: a scanning electron microscope study. J Comp Neurol 1996; 254: 271–8
- Denman-Johnson K, Forge A. Establishment of hair bundle polarity and orientation in the developing vestibular system of the mouse. J Neurocytol 1999; 28: 821–35[Web of Science][Medline]
- Kaltenbach JA, Falzarano PR, Simpson TH. Postnatal development of the hamster cochlea. II. Growth and differentiation of stereocilia bundles. J Comp Neurol 1994; 350: 187–98[Web of Science][Medline]
- Zine A, Romand R. Development of the auditory receptors of the rat: a SEM study. Brain Res 1996; 721: 49–58[Web of Science][Medline]
- Kollmar R. Who does the hair cell's do? Rho GTPase and hair-bundle morphogenesis. Curr Opin Neurobiol 1999; 9: 394–8[Web of Science][Medline]
- Muller U, Littlewood-Evans A. Mechanisms that regulate mechanosensory hair cell differentiation. Trends Cell Biol 2001; 11: 334–42[Web of Science][Medline]
- Self T, Mahoney M, Fleming J, Walsh J, Brown SDM, Steel KP. Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development 1996; 125: 557–66
- Di Palma F, Holme RH, Bryda EC et al. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nat Genet 2001; 27: 103–7[Web of Science][Medline]
- Alagraman KN, Murcia CL, Kwon HY, Pawlowski KS, Wright CG, Woychik B. The mouse Ames waltzer hearing-loss mutant is caused by a mutation of Pdch15, a novel protocadherin gene. Nat Genet 2001; 27: 99–102[Web of Science][Medline]
- Verpy E, Leibovici M, Zwaenpoel I et al. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1c. Nat Genet 2000; 26: 51–5[Web of Science][Medline]
- Avraham KB, Hasson T, Steel KP et al. The mouse Snells waltzer deafness gene encodes an unconventional myosin required for structural integrity of the inner ear hair cells. Nat Genet 1995; 11: 369–75[Web of Science][Medline]
- Self T, Sobe T, Copeland NG, Jenkins NA, Avraham KB, Steel KP. Role of myosin VI in the differentiation of cochlear hair cells. Dev Biol 1999; 214: 331–41[Web of Science][Medline]
- Wells AL, Lin AW, Chen LQ et al. Myosin VI is an actin-based motor that moves backwards. Nature 1999; 401: 505–8[Medline]
- Probst FJ, Fridell RA, Raphael Y et al. Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 1998; 280: 1444–7
[Abstract/Free Full Text] - Beyer LA, Odeh H, Probst FJ et al. Hair cells in the inner ear of the pirouette and shaker 2 mutant mice. J Neurocytol 2000; 29: 227–40[Web of Science][Medline]
- Littlewood-Evans A, Muller U. Stereocilia defects in the sensory hair cells of the inner ear in mice deficient in integrin 8ß1. Nat Genet 2000; 24: 424–8[Web of Science][Medline]
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