Sensory hair cells (HCs) and their associated nonsensory supporting cells (SCs) exhibit a typical mosaic pattern in each of the sensory patches in the inner ear. Notch signaling has been considered to conduct the formation of this mosaic pattern through one of its famous functions, known as 'lateral inhibition'. The two Notch ligands Delta-like1 and Jagged2 are believed to act synergistically at the stage of cell diversification in mammals. In addition, many current studies suggest that Notch signaling has another inductive, but not inhibiting, role in the determination of the prosensory region, which precedes the cell diversification of HCs and SCs and Jagged1 is thought to be an essential ligand in this process. Earlier in ear development, the first cell fate determination begins with the delamination of the neuroblasts from the otic epithelium. The delaminated neuroblasts migrate and coalesce to form cochleovestibular ganglion. Notch signaling pathway is thought to function during the delamination through its lateral inhibitory mechanism. Recently, many experiments examining Notch-related gene expression patterns and direct functional analyses of genes have revealed multiple important functions of Notch in inner ear development. Here, we survey a series of studies and discuss the issues that remain to be elucidated in the future.

INTRODUCTION: STRUCTURE AND DEVELOPMENT OF MAMMALIAN INNER EAR

The mammalian inner ear is a finely structured organ, which consists of a turned cochlea, a central vestibule including saccule and utricle, three semicircular canals that are positioned at right angles to each other and a dorsally protruding endolymphatic duct and sac. In the inner ear, there are three different kinds of sensory regions: the organ of Corti, lining the cochlear duct; the maculae, contained within the saccule and utricle; the cristae, located at the base of each semicircular canal. The macula sacculi, macula utriculi, and the cristae of semicircular canals are responsible for detecting gravity and linear and angular acceleration, respectively. These five organs are crucial for balance; only one sensory organ, the Organ of Corti, is required for hearing (Fig. 1). All six sensory organs are populated by mechanosensory hair cells (HCs) and their associated supporting cells (SCs). Unfortunately, the production of HCs in the cochlea is completed before birth in mammals. Any subsequent loss of auditory HCs is not corrected, resulting in permanent hearing loss. In the vestibular sensory epithelia of adult mammals, HC regeneration in response to amynoglycoside ototoxicity does occur, although it is extremely limited.^1,2

Figure 1.

Organ of Corti (the auditory sensory epithelium) in an adult mouse cochlea. A single row of inner hair cells (indicated by IHC) is placed on the modiolar side of the epithelium and three rows of outer hair cells (OHC) are placed on the strial side in (more...)

The inner ear is derived entirely from the otic placode, which can be initially recognized as a bilateral thickening of the surface ectoderm near the developing hindbrain at embryonic day (E) 8.5 in mice.³ Once established, the otic placode invaginates to form an enclosed otocyst by E10.5. As the otic vesicle closes, the neuroblasts that will give rise to the cochleovestibular ganglion (CVG) start to delaminate from the ventral region of the otocyst around E9.5 (Fig. 2).^4-6 Almost simultaneously, a narrow extension originates in the dorsomedial region of the otocyst, extending toward the brain to form the endolymphatic duct and sac. Similarly, the cochlear duct forms as an outpocketing from the ventral region of the otocyst and continues to grow until E18. Individual regions in the inner ear under go specialization and develop as the prosensory regions that will contain HCs and SCs (for review see ref. 7). During the growth of the cochlear duct, the cells in the primordial organ of Corti exit the cell cycle between E13.5 and E14.5 to establish a distinct zone of nonproliferating cells delimited by the expression of the cyclin kinase inhibitors p27^Kip1 and p19^Ink4d in the cochlea.^8-11 Subsequently, HCs and SCs differentiate within the sensory primordium to form a precise mosaic cell pattern. Initially, HC progenitors expressing Math1 appear in the mid-basal region of the cochlea at developmental stages co-incident with or just after terminal mitosis.^12,13 Math1, a close homologue of the Drosophila proneural gene atonal, encodes a member of the bHLH (basic helix-loop-helix) family of transcriptional factors. Math1 is absolutely required for the generation of HC progenitors as well as their survival.^13-15 As the development continues, additional HC progenitors start to appear in a stereotypical wave of differentiation, that is, from the mid-basal region to both apical and basal directions.¹² SC progenitors develop in the area surrounding the HC progenitors, although with a small delay and the robust activation of Notch1 was detected in these cells.¹⁶

Figure 2.

Development of mouse inner ear. Inner ear is derived entirely from the otic placode, which can be initially recognized at embryonic day (E) 8.5 in mice. The otic placode invaginates to form an enclosed otocyst by E10.5. As the otic vesicle closes, neuroblasts (more...)

MULTIPLE ROLES OF NOTCH SIGNALING PATHWAY DURING INNER EAR DEVELOPMENT

Determination of Prosensory Region

Jagged1 and Prosensory Determination

Jagged1 (Jag1) and Lunatic Fringe (Lfng) are both components of the Notch signaling pathway, with Jag1 acting as a ligand for Notch and Lfng modulating the activity of some Notch ligands.^29,30 The results of in situ hybridization analyses have shown that Jag1 mRNA^5,22,31 and Lfng mRNA³² are both expressed in patterns compatible with a role in prosensory formation during inner ear development. Functional analyses also revealed that mice heterozygous for two different N-ethyl-N-nitrosourea-induced point mutations in Jag1 gene (slalom³³ and head-turner)³⁴ showed mild defects in the sensory organs, especially the reduction of outer HCs in the cochlea. Because embryos homozygous for mutant alleles of the Jag1 gene do not survive past E11.5, Jag1 cko mutant mice were created using the Foxg1-Cre mouse line to express Cre-recombinase in early otocysts.^28,35 In Jag1 cko mice, no HCs or SCs were found at the basal turn of the cochlea, while the number of HCs and SCs was reduced at the apical turn. In the vestibular region, the cristae of semicircular canals were completely lacking and the utricular macula was extremely small. As the saccule and its macula were also mildly affected, the formations of all the six sensory regions of the inner ear were affected to various degrees in Jag1 cko inner ears. Moreover, markers of the prosensory domain, such as Sox2 and the cyclin-dependent kinase inhibitor p27^Kip1, are down regulated in Jag1 cko inner ears. These results suggested that Jag1 is likely to be essential for the determination of the prosensory region in the inner ear.

Role of Notch Signaling in Induction for Prosensory Region

As Jag1 is a Notch ligand, the above-described results imply that Jag1-mediated Notch signaling is essential for establishing the prosensory regions in both of the cochlea and the vestibule. Consistent with this hypothesis, in vitro inhibition of the Notch signaling in cochlear explants with the γ-secretase inhibitor DAPT during early developmental stages reduced the number of HCs and SCs that develop.³⁶ In gain-of-function studies using the constitutively active, intracellular domain of Notch1 (NICD), NICD induced the expression of prosensory markers when over-expressed in the embryonic mouse cochlea,³⁷ and caused the formation of ectopic sensory patches in embryonic chickens.³⁸ These studies support an inductive role for Notch signaling in the formation of prosensory patches within the inner ear, in addition to its subsequent role in lateral inhibitory signaling that determines the HC versus SC fates later during development. Lewis and coworkers have suggested that a Notch-mediated lateral induction mechanism is involved in the prosensory formation: The activation of Notch1 positively regulates the expression of Jag1 autonomously, gradually strengthening the Notch1 activation and the expression of Jag1 in the prosensory cells.^18,38,39 However, this hypothesis has not been tested in long term with direct gain of function in mammals.

In 2010, a Cre-/loxP approach was used to conditionally activate the Notch pathway in nonsensory regions of mouse inner ear epithelia during different stages of otic vesicle morphogenesis.⁴⁰ The Rosa^Notch transgenic mouse yielded a heritable, constitutive co-expression of NICD and nuclear GFP in the presence of Cre-recombinase. The authors selected a FoxG1Cre transgenic line that expresses Cre-recombinase in early otic vesicles and several other regions of embryos and found that the broad ectopic activation of Notch at very early stages caused induction of prosensory markers, such as Sox2 and Hey1 throughout the entire otic epithelium. Unfortunately, as Foxg1Cre; Rosa^Notch embryos did not survive past E13.5, they had to use an hGFAPCCre transgenic line that provides a more restricted pattern of recombination in the nonsensory region of the developing inner ear during later stages. They observed that at intermediate stages of otic morphogenesis, the activation of Notch1 in a nonsensory region led to the induction of ectopic sensory patches containing HCs and SCs. Moreover, they demonstrated that the activation of Notch1 in isolated nonsensory cells induced the lateral induction of Jag1 in adjacent cells. Another group of the researchers also showed that NICD expression resulted in ectopic HCs and SCs in nonsensory regions of the cochlea and vestibule using a combined Tet-On (tetracycline-on)/Cre induction system in mice.⁴¹ These recent reports substantiate the hypothesis that Jag1-Notch-mediated lateral induction may propagate and maintain the prosensory character during inner ear development in both mice and chicks.

Possible Effectors of the Notch Signaling Pathway in the Context of Early Prosensory Formation

Though Jag1-dependent Notch activation has been revealed to be important for prosensory determination during the earlier stage of cochlear development, little is known about the effectors of the Notch pathway in this context. The Notch effectors Hey1 and Hey2 (sometimes referred to as Hesr1 and Hesr2) have been identified as likely mediators of Notch signaling at this stage, mainly based on the expression patterns.³⁶ However, the presumed functional redundancy and early embryonic lethality made a definitive loss-of-function analysis impossible. Another Notch signaling mediator, Hes1, is broadly expressed during the early otocyst stages and may also be involved in defining the prosensory domain.^24,42 A cyclin-dependent kinase inhibitor, p27^Kip1, is also known to demarcate the prosensory region in the cochlear primordium, which consists of the sensory progenitors that have completed their terminal mitoses.^9,10 Hes1 reportedly promotes precursor cell proliferation through the transcriptional down-regulation of p27^Kip1 in the thymus, liver and brain.⁴³ We showed that Hes1, not Hes5 was weakly expressed at the time of onset of p27^Kip1 expression and the expression pattern of Hes1 prior to cell differentiation was similar to that of activated Notch1. In addition, p27^Kip1 was up-regulated and the number of BrdU-positive S-phase cells was reduced in the developing cochlear epithelium of Hes1-null mice.²⁴ The results suggest that Hes1, as one of the effectors of the Notch pathway, may contribute to the adequate proliferation of sensory precursor cells via the potential transcriptional down-regulation of p27^Kip1 expression and may play a pivotal role in the correct prosensory determination.

The HMG-box transcription factor Sox2^{44, 45} has also been thought to play an important role in prosensory formation based on its expression pattern during inner ear development and the absent or severely disturbed prosensory patches in two mouse Sox2 mutant lines, LCC and Ysb.⁴⁶ As the expression of Sox2 is markedly reduced in Jag1 cko mutant mice,³⁵ it is supposed that Sox2 may function downstream of the Jag1-Notch1 signaling pathway during prosensory formation. However, the mechanism of the contribution of Sox2 in this context still remains to be elucidated.

Biphasic Regulation of Cell Proliferation by the Notch Signaling Pathway during the Inner Ear Development

We investigated the spatio-temporal expression pattern of activated Notch1 (actN1) during the mouse cochlear development.²⁴ The results showed that actN1 was diffusely observed in the prosensory region and greater epithelial ridge (GER) during the early developmental stage and Notch1 was activated robustly in SC progenitors at a later stage of cell diversification after E14.5 (Fig. 3). The level of Notch1 signaling switched from a diffuse state to a robust state at the time of cell cycle exit, when the Notch pathway started to promote cell diversification through lateral inhibition.²⁴ On the other hand, the diffuse pattern of Notch1 activation before E13.5 was closely related to the expression of Hes1 as well as Jag1. Thus, as discussed in the former chapter, the diffuse activation of Notch1 should be critical for the prosensory formation by continuing the adequate proliferation of sensory precursor cells.²⁴ Interestingly, the higher level of Notch1 activation during the later stage of cochlear development was supposed to inhibit excessive cell division in several studies. A huge increase in HCs was observed in Dll1^+/- Jag2^-/- cochlea and the authors suspected that their observation resulted from the inhibition of excessive cell division via the Notch pathway during cell diversification.²⁷ A similar conclusion was drawn in a study examining in vitro culture of mouse fetal cochleae and the reversible inhibition of the Notch-signaling pathway using inhibitors of γ-secretase and TNF-α-converting enzyme.⁴⁷ Previous reports have revealed that Notch signaling has similar biphasic roles during the development of the central nervous system (CNS).^{48, 49} We propose that the deletion of the Hes1 allele may suppress cell proliferation during the period of prosensory formation and that excessive cell division might occur during the next cell diversification stage, resulting in the relatively mild increase in HCs observed in Hes1^-/- mice at E17.5 in previous studies.^23,24,26

Figure 3.

Spatio-temporal activation pattern of Notch1 during the mouse cochlear development. We detected the expression patterns of the activated form of Notch1 (actN1) by immunohistochemistry using an antibody that specifically recognizes the processed form of (more...)

NOTCH SIGNALING PATHWAY AND THE INNER EAR REGENERATION

The production of HCs in the cochlea is finished before birth in mammals. Any subsequent loss of auditory HCs is not compensated, resulting in irreversible hearing loss. In contrast, many nonmammalian vertebrates readily regenerate HCs into adulthood and HC regeneration has been most thoroughly studied in birds (see review ref. 57). In birds, when acoustic trauma or ototoxic drugs destroy HCs, SCs give rise to new HCs in two different ways. First, SCs are directly converted into new HCs through a method described as transdifferentation.^{57, 58} A few days later, SCs adjacent to the dying HCs re-enter the cell cycle, dividing asymmetrically to generate new HCs and SCs.^{60, 61} In the normally quiescent bird auditory epithelium, HC regeneration seems to re-activate developmental programs and the Notch signaling pathway is probably one of the best candidates for investigation. During development, Notch receptor activation suppresses HC diversification through the up-regulation of the Hes genes, which are potent inhibitors of Math1. As a result, the control of the Notch pathway, such as through the deletion of Notch ligands, leads to supernumerary HCs. Correspondingly, during zebrafish lateral line⁶² and chick basilar papilla (BP; auditory epithelium) HC regeneration,⁶³ the inhibition of the Notch signaling pathway increases the production of new HCs. Daudet and co-researchers showed that the blockade of Notch signaling by DAPT had no direct effect on SC division after HC damage in organ cultures of chick BP.⁶³ However, DAPT caused the excessive regeneration of HCs at the expense of SCs, through both mitotic and nonmitotic mechanisms with the up-regulation of Delta1 and Hes5 genes. They also confirmed that the inhibition of γ-secretase in undamaged BP does not trigger HC production. Conversely, the over expression of NICD in SCs after damage caused them to maintain their phenotype and inhibited HC regeneration. These data imply that Notch signaling controls the switches of the cell diversification, but may not directly regulate the cell division in the regeneration of BP. The authors supposed that another signal (Q signal; signal for quiescence), which is independent of Notch signaling (N signal), functions during quiescence and regeneration and inhibits SCs from direct transdifferentiation into HCs and from cell division to product HC and SC progenitors.

In mammals, the applications of DAPT to explants of embryonic and neonatal organ of Corti resulted in the robust production of supernumerary HCs in the case of mice.^47,64 Continuous inhibition through the application of DAPT also seems to induce the mitogenic proliferation of SCs in the cultures of embyronic organ of corti.⁴⁷ However, experiments on damaged adult guinea pig organs of Corti are disappointing; local application of a γ-secretase inhibitor, MDL28170, resulted in the formation of very limited ectopic HCs in the inner sulcus region.⁶⁵ The results might imply that when HCs are injured in adult mammals, the Q-signal that has been described in the case of chicks cannot be adequately weakened by some unknown factors. We might be able to elucidate these factors by investigating other signaling pathways that are act reciprocally with the Notch signaling pathway during inner ear development.

CONCLUSION

Auditory and vestibular sensory organs in the inner ear are composed of mechanosensory hair cells (HCs) and associated supporting cells (SCs). HCs are not neighboring each other and are separated by SCs. As a result, they form a typical mosaic cell pattern, which have intrigued the researchers to think that Notch mediated inhibitory mechanism called 'lateral inhibition' should play a pivotal role in HC and SC differentiation during inner ear development. Recent about 15 years' progress of molecular and developmental biology have revealed that the Notch signaling pathway have multiple important roles in developing inner ear, including the determination of prosensory region, the regulation of cell proliferation as well as the cell diversifications. Unfortunately, mammalian auditory epithelium do not have regenerative capacity when they have been injured by noise or modern drugs, contrasting to that of non-mammalian vertebrates including birds, in which HC regeneration seems to reactivate the developmental programs. Some researchers tried to induce HC regeneration in damaged adult mammalian cochlea via manipulating the Notch signaling pathway, for example, by applying γ-secretase inhibitors. However, they have not succeeded in the HC restoration yet. By investigating other factors and signaling pathways that act reciprocally with the Notch signaling pathway during inner ear development, we might be able to make progress in the regenerative medicine for hearing deficient.

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