Cellular & Molecular Medicine: Open access

Keywords

Hair cells; Regeneration; Epigenetic; Signaling pathways

Sensory hair cell loss in the inner ear is the major cause of hearing and vestibular impairment, and the sensory hair cells are sensitive to a wide variety of noxious insults, including aging, illness, acoustic trauma, noise exposure, genetic disorders, and ototoxic drugs. Normally hair cells do not regenerate in adult mammals [1] but a very limited degree of hair cell regeneration can occur in vestibular sensory epithelium and in early postnatal mammalian cochlea [2-7], thus hair cell loss in humans and other mammals lead to permanent deafness and / or balance disorders. In contrast, spontaneous regeneration of hair cells occurs in many non-mammalian vertebrates such as amphibians, birds, and fish [8-11]. The precise mechanisms responsible for initiating and maintaining – or preventing – hair cell regeneration are still not completely understood. It has been shown that many candidate molecules and pathways are involved in the regeneration of hair cells, including HDACs, LSD1, Atoh1, Wnt, Shh, Fgf and Notch signaling pathways. Thus, a better understanding how epigenetic and genetic factors impact hair cell regeneration might point to rational targets for reversing hearing problems in humans.

Redundant roles of HDACs in hair cell regeneration

Coordinated and strictly regulated gene expression is essential for diverse biological processes such as cellular survival, differentiation, development and regeneration of tissues in vertebrates, and epigenetic chromatin remodeling is an important regulation process that regulates gene transcription Kouzarides [12]. In most cases, chromatin architecture regulation are achieved by histone posttranslational modifications, including methylation, acetylation, phosphorylation, and ubiquitination, which alter histones interaction with DNA and nuclear proteins [13,14]. Histone modifications have been implicated in the regulation of cell fate decisions, as well as normal tissue development and maintenance. Aberrant histone modifications have been associated with pathologies and diverse human diseases such as cancer. Histone acetylation is one of the most common histone modifications and is essential for many developmental processes. Two types of enzymes responsible for regulating histone acetylation states are histone acetyltransferases (HATs) and histone deacetylases (HDACs). Generally, HATs add acetyl groups to lysine residues and enhance gene transcription, while HDACs remove those acetyl groups from histone tails repressing gene transcription. HDACs are subdivided into four major classes based on homology to their yeast counterparts [15-17]. Class I HDACs, including HDAC1, -2, -3, and -8, are expressed widely across cell types and play an important role in regulating cell survival and proliferation [18,19]. Class II HDACs, including HDAC4, -5, -6, -7, -9, and -10, are defined by their similarity to the yeast HDA1 and function as a shuttle between nucleus and cytoplasm [20,21]. Class III are referred to as the sirtuins, and requires NAD+ for its enzymatic activity. Class IV, HDAC11, shares similarity with both class I and II enzymes [18]. HDACs have specific functions in normal embryonic development [22]. For instance, Class I HDACs have been shown to be involved in the regulation of multiple aspects of developmental processes, including neuronal differentiation and liver morphogenesis [23-25]. Class I HDACs are also required for proper formation of the eye, craniofacial cartilage, pectoral fin, heart, and exocrine pancreas [26-30]. The vast majority of studies of the functions of HDACs have focused on the potential of HDAC inhibitors (HDACis) and knockdown or overexpression of HDACs. Aberrant expression of HDACs has been reported in various cancer types [31-35] and HDACis are currently attracting enormous attention as anticancer drugs because of their ability to inhibit cancer cell proliferation, induce cell-cycle arrest, and cause cell death [36- 38]. Although HDAC activity has been demonstrated to play a vital role in cellular differentiation, apoptosis, migration, proliferation, survival, as well as cell cycle regulation via the formation of complexes with various transcription factors [22,39], very little is known about histone regulation in the inner ear. Previous studies have shown that aminoglycoside antibiotics treatment decreased histone acetylation in the nuclei of mammalian hair cells [40,41]. HDAC inhibitors were shown to increase acetylation of core histones and rescue hair cells from damage by aminoglycoside antibiotics [41,42]. More recent work suggested that HDACs are expressed within the organ of Corti during the first postnatal week of development, and may help to develop new therapeutics in the treatment of hearing loss and hearing regeneration [43]. In the auditory field of non-mammalian vertebrates, two recent studies describe that HDACs are required for zebrafish posterior lateral line (PLL) formation and pharmacological inhibition of HDAC activity disrupts PLL primordium migration, suppresses primordial cell proliferation, and reduces hair cell numbers within neuromast [44,45]. HDAC inhibition causes a significant reduction in cell proliferation by altering the expression of cell cycle regulatory proteins [45]. He et al. showed the HDAC1 expression in the developing otic vesicles of zebrafish and investigated the function of HDAC1 during inner ear morphogenesis [46]. HDAC1 knockdown results in smaller otic vesicles, abnormal otoliths, malformed semicircular canals, and fewer sensory hair cells, and HDAC1 dysregulation causes attenuated expression of a subset of key genes required for otic vesicle formation during zebrafish organogenesis. In mouse auditory system, HDAC3 can be detected in the otic vesicles at embryonic day 10, and this has provided the basis for further studies of the biological functions of HDAC3 in the development of the auditory organs [47]. Recently reported the presence of HDAC3 in the zebrafish PLL primordium and newly deposited neuromasts, and indicated that HDAC3 has essential roles in zebrafish PLL formation by activating Fgf signaling [48]. Building upon the crucial roles of HDACs during development, numerous studies have focused on HDACs in the modulation of many tissues regeneration. Recent work in Xenopus tail regeneration suggested that HDAC1 is expressed during the early stage of regeneration and that pharmacological blockage of HDACs could inhibit regeneration and induce aberrant expression of genes that are known to be critical for tail regeneration [49]. It has been reported that HDAC activity is required for the regeneration of sensory epithelia in the avian utricle [50]. Histone deacetylation is a positive regulator of regenerative proliferation, and inhibition of HDACs is sufficient to prevent supporting cells from entering into the cell cycle. A subsequent study on damaged zebrafish lateral line system demonstrated that inhibition of HDAC function by TSA, a potent class I and II HDAC inhibitor, can affect hair cell regeneration in neuromasts by altering the histone acetylation state. Studies conducted using bromodeoxyuridine (BrdU) labeling show that hair cells in lateral line and inner ear can undergo continuous proliferation [51-53]. However, pharmacological inhibition of HDACs results in decreased proliferation of the progenitor cell population in regenerated neuromasts. The reduction in supporting cell proliferation causes a reduction in the number of regenerated hair cells but does not affect cell death. These data indicate that HDACs are required for hair cell regeneration in the zebrafish lateral line neuromasts after neomycin-induced cell death and that HDACs might be potential therapeutic targets for the induction of hair cell regeneration and supporting cell proliferation. Thus far, the precise mechanisms by which individual HDACs affect hair cell regeneration are still not clear. Further analysis is needed to identify the specific HDACs that regulate hair cell regeneration, which should aid in the elucidation of regeneration mechanisms in the human inner ear. Identification of the specific target genes that are being regulated by HDACs should also help to elucidate the role these genes play in the regenerating zebrafish neuromast. Recent advances in microarray or RNA-seq has provided important clues for understanding epigenetic regulation of hair cell regeneration [54].

Functions of histone methylation in hair cell regeneration

Histone methylation is a major covalent of histone modification that have been linked to the regulation of gene transcription. Histone methylation is catalyzed by the histone methyltransferases, while the removal of methyl groups from histone lysine residues is catalyzed by the histone demethylases [55]. Recent studies have demonstrated the specific function of histone methyltransferases /demethylases in many cellular processes such as cell cycle regulation, differentiation, survival, death, and proliferation [56,57]. Lysine-specific demethylase 1 (LSD1; KDM1; AOF2) was the first discovered histone demethylase and belongs to the superfamily of the flavin–dependent monoamine oxidases [58]. The enzyme is able to modulate gene expression through demethylation of lysines 4 and 9 of histone H3 by interacting with a variety of molecular partners [58-64]. Some studies have demonstrated that LSD1 plays important roles in many important cellular processes, including proliferation and differentiation [65-67]. It has been reported that LSD1 is implicated in neural stem cell proliferation. Either chemical inhibition of LSD1 activity or small interfering RNA (siRNA) knockdown of LSD1 expression led to dramatically reduced neural stem cell proliferation [68]. Numerous studies have shown that down regulation of LSD1 might promote the initiation and invasion of various tumors, such as colorectal, neuroblastoma, lung, gallbladder and prostate cancer [69-75]. In addition, recent work found that maintenance of high levels of histone 3 lys4 dimethylation (H3K4me2) through the pharmacological inhibition of LSD1 attenuates neomycin-induced hair cell apoptosis [76]. During hair cell development, it has been reported that inhibition LSD1 activity suppresses cell proliferation and decreases hair cell numbers in the zebrafish lateral line [77]. Given the integral roles of LSD1 in hair cell differentiation, extensive work has been undertaken to characterize its involvement in hearing regeneration. He and colleagues demonstrated that mitotic hair cell regeneration after neomycin damage decreases when 2-PCPA is used to inhibit LSD1 activity in the zebrafish lateral line system. LSD1 play a crucial role in cellular proliferation by regulating the expression of genes such as p21, p27, CDK2, CDK4, CDK6, cyclinD1, and cyclinE1 [78]. This work also suggested that the underlying mechanism behind 2-PCPA’s effects on hair cell regeneration might be through inactivation of both the Wnt/β-catenin and Fgf signaling pathways. This study provides new insights into the mechanisms of hair cell regeneration in zebrafish and suggests that epigenetic regulators might be a novel therapeutic target for the treatment of hearing loss.

The role of Atoh1 transcription factor in hair cell regeneration

Atoh1 is recognized as a single master switch necessary and sufficient to control the hair cells development [79-81]. In the inner ear, Atoh1 is expressed in hair cells as well as in a subpopulation of precursors. Disruption of Atoh1 gene in precursor cells result in a failure of hair cell formation in the cochlea [82,83]. Although, the transient expression of Atoh1 during development is essential for the survival and formation of functional hair cells, the expression becomes more crucial during hair cells maturation and during the development of stereociliary bundles [84,85]. In contrast, overexpression of Atoh1 triggers the formation of functional mechanosensory hair cells in embryonic and neonatal mouse cochlea and most of the new hair cells acquired hair cell fate from two supporting cell types, including pillar cells and deiter cells [82,86-88]. Based on their critical role in hair cell development, various studies have focused on defining the role of Atoh1 in hair cell regeneration after damage in mature cochlea. The viral mediated delivery of Atoh1 gene in nonsensory cells stimulate the hair cells regeneration and partially restore the hearing in ototoxic damage model of mature guinea pig [89]. However, it is necessary to have the presence of supporting cells in organ of Corti to further transdifferentiate into hair cells [90]. Recently, another study showed that the effectiveness of viral mediated Atoh1 delivery is inconsistent and dependent on timing of expression after ototoxic damage in mature cochlea [91]. Collectively, these findings suggest that the Atoh1 critically promote the regeneration and survival of hair cells; however, it’s not sufficient alone to fully convert the nonsensory cells into mature hair cells after severe ototoxic damage.

The role of Wnt signaling pathway in hair cell regeneration

Wnt signaling pathway is indispensable for various modes of operation during development and adult life including proliferation, determining the cell fate, maintaining progenitors and participation in cellular polarization. Wnt pathway triggers upon binding of wnt ligands to their respective Frizzled transmembrane receptor and generally categorized into distinct intracellular canonical and non-canonical signaling pathways [92-94]. Our primary focus is to discuss the role of canonical Wnt pathway in hair cells regeneration. Non-mammals such as fish and birds retain the ability to regenerate hair cells and restore hearing spontaneously after damage [8,95]. However, adult mammals lack the competence to regenerate hair cells after ototoxic insult [96]. The β-catenin dependent canonical pathway regulates the cell fate and proliferation in sensory epithelium [97]; the nuclear translocation and the binding of β-catenin to TCF/LEF transcription factor complex activates the downstream expression of wnt target genes, including Lgr5, Axin2. Multiple studies, in recent years have reported that the canonical Wnt pathway is involved in hair cell regeneration. The expression of Wnt target gene Lgr5, Lgr6 and Axin2 in cochlear supporting cells indicate the existence of active Wnt signaling pathway in neonatal cochlea [98,99]. Lgr5+ cells have been demonstrated as an enriched population of hair cell progenitors both in vitro and in vivo [7,100,101]. The addition of Wnt agonist enhanced the proliferation and hair cell regeneration efficiency of Lgr5+ progenitor cells in the inner ear [100-102]. Moreover, the forced expression of β-catenin triggers the Atoh1 expression in colonies derived from isolated supporting cells and promotes the hair cells formation in vivo and vitro [101,103,104]. Similarly, the conditional overexpression of β-catenin in Lgr5+ progenitors expands the proliferation and regeneration capability of supporting cells to generate hair cells [100,101,105]. Another Wnt downstream target gene, axin2 has also been reported to label another inner ear stem cell population, which named tympanic border cells; and the isolated the Axin2+ cell also retain the capacity to regenerate hair cells in the inner ear [100]. In sum, these studies in regenerating sensory hair cells in neonatal mice cochlea revealed that the canonical Wnt signaling have the potential to stimulate hair cells regeneration by capitalizing the supporting cell pool, which is known to be enriched with hair cells precursors. However it remains to be examined whether this pool of supporting cell which harboring the hair cells progenitors can regenerate the new hair cells in response to Wnt activation in damaged adult mammalian cochlea.

The role of notch signaling pathway in hair cell regeneration

Notch signaling pathway determines the sensory region in the inner ear and regulates the differentiation of mechanosensory hair cells [105-107]. Notch signaling arbitrates the process of lateral induction by activating Jagged 1, which is necessary to specify prosensory cells [107]. It seems that Notch signaling is mandatory to establish the size and maintenance of prosensory region. The Loss of Notch signaling during early development results in complete absence or partially smaller sensory region having decrease hair cells and supporting cells [107,108]. In contrast, the transient overexpression of NICD in mouse inner ear formed an ectopic hair cells and supporting cells in sensory region [108,109]. The process of lateral inhibition in inner ear established the mosaic pattern of hair cells and supporting cells. During development, hair cells expressed Delta1 and Jagged ligands that interact with Notch receptor on supporting cells, which releases the NICD in supporting cells that up-regulate the expression of Hes1 and Hes5. Accumulation of Hes1 and Hes5 inhibit the expression of Atoh1 in supporting cells thus preventing it from hair cell formation [107,110]. Apart from their involvement in development, Notch signaling has been considered to define their role in hair cell regeneration. Damage mediated via aminoglycoside drug triggers the increase of proteins involved in Notch activation including Jagged 1, Hes1, and Hes5 [111]. Another study highlighted that the inhibition of Notch signaling through γ-secretase inhibitor results in transdifferentiation of supporting cells into hair cells [112]. The expression of Atoh1 transcription factor seems to be increased upon Notch inhibition and stimulate the regenerative potential of supporting cells in drug damage model [113]. In Utricle, the down-regulation of Hes5 and up-regulation of Atoh1 promote the hair cells regeneration upon treatment with neomycin and γ-secretase inhibitor [114,115]. In addition, Few studies have also shown that the conditional deletion of Rbpsuh gene or use of γ-secretase inhibitor in undamaged cochlear model encourage the supporting cells to acquire hair cell fate [116,117]. Taken together, these findings suggest that the localized Notch activity significantly participated in inhibiting direct transdifferentiation of supporting cells into hair cells. However, promising strategies need to be defined in order to inhibit Notch signaling to further disrupt the lateral inhibition and allowing the supporting cells to regenerate hair cells in mammalian cochlea.

The role of Shh signaling pathway in hair cell regeneration

nic Hedgehog pathway is essential for determining the sensory hair cell fate and patterning during inner ear development [118]. Shh was first reported to be expressed in spiral ganglion neuron cells with gradually decreased levels from basal to apical neurons [119]. Sonic hedgehog signaling begins when specific stimuli trigger the cells to secrete Shh ligand, which binds to the membrane receptor patched 1, resulted in activation of another membrane protein smoothened. This combination of membrane protein stimulates the downstream pathway where Gli transcription factors translocate to the nucleus and regulate the expression or repression of Shh target genes. Knowledge about the role of Shh signaling in hair cell regeneration is largely remains unknown. One study demonstrated that the exogenous Shh treatment of neonatal cochlea, in explant culture, induces the regeneration of hair cells by inhibiting the expression of retinoblastoma protein after neomycin damage [120]. Several studies have been reported to characterize the role of Shh signaling in guiding prosensory cells formation during development. Cochlea isolated from Gli3 mutant mice treated with Shh signaling inhibitor, in explant culture, showed a large sensory epithelium, while the treatment with Shh halts their expansion [121]. Another study showed that the conditional deletion of smo gene in the cochlea displayed an accelerated differentiation of hair cells in apex. Nevertheless, the expression of constitutively active allele of smo in the cochlea exhibited no rows of outer hair cells, which suggests that it restricts the differentiation of outer hair cells [122]. Collectively, these studies highlighted the role of Shh signaling during the development of cochlea. However, there are a lot of unaddressed questions need to be answered regarding their involvement in hair cells regeneration in postnatal cochlea.

The role of FGF signaling pathway in hair cell regeneration

Fibroblast growth factor (FGF) signaling pathway is critical for the development of the inner ear, especially when the otic placode thickened from ectoderm and invigilate to form otic vesicle. It further participates in the morphogenesis of inner ear [123- 125]. The FGF pathway becomes activated when the FGF protein signal through the four known FGF receptors, including FGFR1, FGFR2, FGFR3 and FGFR4 Pickles [126]. Multiple studies have illustrated that the targeted deletion of Fgfr1 gene disrupts the prosensory cell formation, which later generates fewer hair cells and supporting cells in the organ of Corti; because in the absence of FGFR1 receptor, the cochlear duct is unable to maintain the pool of sensory precursor cells [127,128]. Similarly, the deliberate interruption of FGF signaling during embryonic development using FGF receptor inhibitor severely reduce the hair cells and supporting cells formation. Interruption of FGF signaling also reduces the Atoh1 expression [129], suggesting the involvement of FGF signaling in hair cells differentiation. The role of FGF signaling during hair cell regeneration has not been thoroughly defined in mammalian cochlea. It has been reported that fgfr3 is up-regulated in the cochlea after acoustic damage [130]. However it still remains unclear how it affects the hair cell regeneration in cochlea. On the contrary, some studies have reported the decreased expression of Fgfr3 in chicken and zebra fish lateral line after damage [131,132]. Likewise, reduced expression of Fgfr3 and Fgf20 was reported when analyzed the transcriptome expression profiles, during the regeneration of chicken utricle in vitro [54]. In sum, these studies highlighted the major involvement of FGF signaling during inner ear development, in order to govern the prosensory cell formation and hair cell differentiation. However, the detailed role of FGF signaling in regulating the hair cell regeneration still need to be further investigated in the future.

Reciprocal interaction between Wnt and notch pathway in hair cell regeneration

Cellular signaling pathways are interconnected with each other and recent studies have been focused on the simultaneous modulation of these signaling pathways in order to induce the hair cell regeneration. The reciprocal interaction between the Wnt and Notch pathway during cell fate determination have been thoroughly studied in various tissues [117,133-135]. Previous finding shows that there are some similarities and coordination in their actions. Wnt signaling acts upstream of Notch and it regulates the Notch genes in a positive manner such as β-catenin regulates the expression of Jag1 in otic placode and during prosensory cell formation [133,136]. The canonical Wnt signaling pathway induces proliferation of supporting cell to generate hair cells in neonatal cochlea [100,106]. Similarly, the down-regulation of Notch signaling also stimulates the supporting cells to proliferate and generate hair cells [113]. Though, Wnt signaling have no effects on adult mice, while suppression of Notch signaling turn the supporting cells into hair cells via transdifferentiation [113]. A current study pinpointed that Notch inhibition up-regulates the β-catenin expression, which further stimulates the proliferation of Wnt responsive Lgr5+ supporting cells to mitotically regenerate hair cells in postnatal cochlea [118]. Another study shows that Notch inhibition activates regenerative potential of supporting cells to form hair cell, which also moderately, depends on wnt signaling [135]. A recent study in zebrafish also reveals that the hair cell regeneration requires the localized interaction between the Wnt and Notch signaling [137]. These finding suggests the interplay of Wnt and Notch pathway may evoke the regenerative potential of neonatal supporting cells. However, the precise molecular mechanism behind this interaction still need to be further investigated in the future.

Reciprocal interaction between Atoh1 and Wnt pathway in hair cell regeneration

The interaction between Atoh1 and Wnt signaling is getting more and more attention in recent years. The involvement of Atoh1 in cell fate determination during development is thoroughly studied [79,82]. However, there is little understanding about their interaction with other pathways and their participation in hair cells regeneration. A study performed during embryonic development reported that the Atoh1 is a Wnt target and the activation of Canonical Wnt signaling via up-regulation of β-catenin positively regulates the expression of Atoh1 [103]. It also generates supernumerary hair cells in cochlea [104] suggesting Wnt signaling works upstream of Atoh1 in order to regulate their expression and ultimately stimulate the proliferation and hair cell differentiation. In postnatal cochlea, one recent study demonstrated that the constitutive expression of Atoh1 together with β-catenin, proliferate and trans-differentiate 10 fold more hair cells from Lgr5+ progenitor cells as compared to previous reports in vivo [138]. Collectively, these findings highlighted the most probable strategy for hair cell regeneration, which is to first activate the Wnt signaling to stimulate the proliferative potential of cochlear supporting cells and further initiate the expression of Atoh1 and inhibit the Notch signaling in order to promote their differentiation potential into hair cells in the mammalian inner ear.

Conclusion

In recent years, tremendous progress has been made in revealing the mechanisms involved in hair cell damage and regeneration. Given that the important roles of epigenetic mechanisms and signaling pathways during differentiation, cellular reprogramming, as well as stem cell maintenance, it seems likely that investigating and manipulating the epigenetic changes together with the signaling pathway during hair cell regeneration may lead to new therapeutic avenue to treat or prevent hearing loss in humans. This review has helped to define the epigenetic regulations and various signaling mechanisms in hair cell regeneration. In addition, understanding how various signaling mechanisms function to modulate sensory hair cell regeneration and how epigenetic regulation affect the complex signaling events have become a major focus for future research toward ultimately functional hair cell regeneration and hearing recovery.

References

1. Roberson DW,Rubel EW (1994) Cell-Division in the Gerbil Cochlea after Acoustic Trauma. American Journal of Otology 15: 28-34.
2. Forge A, Li L, Corwin JT, Nevill G (1993) Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 259: 1616-1619.
3. Warchol M E, Lambert PR, Goldstein BJ, Forge A, Corwin JT (1993) Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 259: 1619-1622.
4. Rubel E W, Dew LA, Roberson DW (1995) Mammalian vestibular hair cell regeneration. Science 267: 701-707.
5. Forge A, Li L, Nevill G (1998) Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs. J Comp Neurol 397: 69-88.
6. Burns J C, Cox BC, Thiede BR, Zuo J, Corwin JT (2012) In vivo proliferative regeneration of balance hair cells in newborn mice. J Neurosci 32: 6570-6577.
7. Cox B C, Chai R, Lenoir A, Liu Z, Zhang L, et al. (2014) Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 141: 816-829.
8. Corwin J T, Cotanche DA (1988) Regeneration of sensory hair cells after acoustic trauma. Science 240: 1772-1774.
9. Balak K J, Corwin JT , Jones JE (1990) Regenerated hair cells can originate from supporting cell progeny: evidence from phototoxicity and laser ablation experiments in the lateral line system. J Neurosci 10: 2502-2512.
10. Harris J A, Cheng AG, Cunningham LL, MacDonald G, Raible DW et al. (2003) Neomycin-induced hair cell death and rapid regeneration in the lateral line of zebrafish (Danio rerio). Jaro-Journal of the Association for Research in Otolaryngology 4: 219-234.
11. Hernandez PP, Moreno V, Olivari FA, Allende ML (2006) Sub-lethal concentrations of waterborne copper are toxic to lateral line neuromasts in zebrafish (Danio rerio). Hear Res 213: 1-10.
12. Kouzarides T (2007) Chromatin modifications and their function. Cell 128: 693-705.
13. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293: 1074-1080.
14. Berger SL (2002) Histone modifications in transcriptional regulation. Curr Opin Genet Dev 12: 142-148.
15. Gray S G , Ekstrom TJ (2001) The human histone deacetylase family. Experimental Cell Research 262: 75-83.
16. Khochbin S, Verdel A, Lemercier C, Seigneurin-Berny D (2001) Functional significance of histone deacetylase diversity. Curr Opin Genet Dev 11: 162-166.
17. Gao L, Cueto MA, Asselbergs F, Atadja P (2002) Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 277: 25748-25755.
18. De Ruijter A J M, Van Gennip AH, Caron HN, Kemp S ,Van Kuilenburg ABP (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochemical Journal 370: 737-749.
19. Gregoretti I V, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis. Journal of Molecular Biology 338: 17-31.
20. Verdin E, Dequiedt F , Kasler HG (2003) Class II histone deacetylases: versatile regulators. Trends Genet 19: 286-293.
21. Lahm A, Paolini C, Pallaoro M, Nardi MC, Jones P, et al. (2007) Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci U S A 104: 17335-17340.
22. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Reviews Genetics 10: 32-42.
23. Cunliffe VT (2004) Histone deacetylase 1 is required to repress Notch target gene expression during zebrafish neurogenesis and to maintain the production of motoneurones in response to hedgehog signalling. Development 131: 2983-2995.
24. Yamaguchi M, Tonou-Fujimori N, Komori A, Maeda R, Nojima Y, et al. (2005) Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development 132: 3027-3043.
25. Farooq M, Sulochana KN, Pan XF, To JW, Sheng D, et al. (2008) Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish. Developmental Biology 317: 336-353.
26. Pillai R, Coverdale LE, Dubey G, Martin CC (2004) Histone deacetylase 1 (HDAC-1) required for the normal formation of craniofacial cartilage and pectoral fins of the zebrafish. Dev Dyn 231: 647-654.
27. Stadler JA, Shkumatava A, Norton WHJ, Rau MJ, Geisler R, et al. (2005) Histone deacetylase 1 is required for cell cycle exit and differentiation in the zebrafish retina." Developmental Dynamics 233: 883-889.
28. Montgomery RL, Hsieh J, Barbosa AC, Richardson JA, Olson EN (2009) Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development. Proceedings of the National Academy of Sciences of the United States of America 106: 7876-7881.
29. Dovey OM, Foster CT, Cowley SM (2010)Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. Proc Natl Acad Sci U S A 107: 8242-8247.
30. Kim YS, Kim MJ, Koo TH, Kim JD, Koun S, et al. (2012)Histone deacetylase is required for the activation of Wnt/beta-catenin signaling crucial for heart valve formation in zebrafish embryos. Biochemical and Biophysical Research Communications 423: 140-146.
31. Krusche C A, Wulfing P, Kersting C, Vloet A, Bocker W, et al. (2005)Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res Treat 90: 15-23.
32. Noh J H, Eun JW, Ryu SY, Jeong KW, Kim JK, et al. (2006) Increased expression of histone deacetylase 2 is found in human hepatocellular carcinoma. Molecular & Cellular Toxicology 2: 166-169.
33. Wilson A J, Byun DS, Popova N, Murray LB, Italien KL, et al. (2006) Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer." J Biol Chem 281: 13548-13558.
34. Fritzsche FR, Weichert W, Roske A, Gekeler V, Beckers T, et al. (2008) Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer 8: 381.
35. Weichert W (2009) HDAC expression and clinical prognosis in human malignancies. Cancer Lett 280: 168-176.
36. Kim DH, Kim M, Kwon HJ (2003) Histone deacetylase in carcinogenesis and its inhibitors as anti-cancer agents. Journal of Biochemistry and Molecular Biology 36: 110-119.
37. Bi G, Jiang G (2006) The molecular mechanism of HDAC inhibitors in anticancer effects. Cell Mol Immunol 3: 285-290.
38. Glaser KB (2007) HDAC inhibitors: Clinical update and mechanism-based potential. Biochemical Pharmacology 74: 659-671.
39. Hayakawa T , Nakayama J (2011)Physiological roles of class I HDAC complex and histone demethylase. J Biomed Biotechnol 2011: 129-383.
40. Jiang H, Sha SH, SchachtJ (2006)Kanamycin alters cytoplasmic and nuclear phosphoinositide signaling in the organ of Corti in vivo. J Neurochem 99: 269-276.
41. Chen F Q, Schacht J, Sha SH (2009) Aminoglycoside-induced histone deacetylation and hair cell death in the mouse cochlea. J Neurochem 108: 1226-1236.
42. Layman WS, Williams DM, Dearman JA, Sauceda MA, Zuo J (2015)Histone deacetylase inhibition protects hearing against acute ototoxicity by activating the Nf-B pathway. Cell Death Discov 1.
43. Layman WS, Sauceda MA , Zuo J (2013)Epigenetic alterations by NuRD and PRC2 in the neonatal mouse cochlea. Hear Res 304: 167-178.
44. He Y, Wu J, Mei H, Yu H, Sun S, et al. (2014)Histone deacetylase activity is required for embryonic posterior lateral line development. Cell Proliferation 47: 91-104.
45. He YZ, Mei HL, Yu HQ, Sun S, Ni WLet al. (2014)Role of histone deacetylase activity in the developing lateral line neuromast of zebrafish larvae. Experimental and Molecular Medicine 46.
46. He Y, Tang D, Li W, Chai R, Li H (2015d)Histone deacetylase 1 is required for the development of the zebrafish inner ear. Scientific Reports.
47. Murko C, Lagger S, Steiner M, Seiser C, Schoefer C,et al. (2010)Expression of class I histone deacetylases during chick and mouse development. Int J Dev Biol 54: 1527-1537.
48. He Y, Wang Z, Sun S, Tang D, Li W, et al. (2015)HDAC3 Is Required for Posterior Lateral Line Development in Zebrafish. Mol Neurobiol.
49. Tseng AS, Carneiro K, Lemire JM, Levin M (2011)HDAC Activity Is Required during Xenopus Tail Regeneration. Plos One.
50. Slattery E L, Speck JD, Warchol ME (2009)Epigenetic Influences on Sensory Regeneration: Histone Deacetylases Regulate Supporting Cell Proliferation in the Avian Utricle. Jaro-Journal of the Association for Research in Otolaryngology 10: 341-353.
51. Jorgensen JM (1991)Regeneration of Lateral Line and Inner-Ear Vestibular Cells. Ciba Foundation Symposia 160: 151-170.
52. Lanford PJ, Presson JC, Popper AN (1996)Cell proliferation and hair cell addition in the ear of the goldfish, Carassius auratus. Hearing Research 100: 1-9.
53. Sun HF, Lin CH, Smith ME (2011)Growth Hormone Promotes Hair Cell Regeneration in the Zebrafish (Danio rerio) Inner Ear following Acoustic Trauma. Plos One.
54. Jiang L, Romero-Carvajal A, Haug JS, Seidel CW, Piotrowski T (2014) Gene-expression analysis of hair cell regeneration in the zebrafish lateral line. Proc Natl Acad Sci U S A 111: E1383-1392.
55. Agger K, Christensen J, Cloos PA, Helin K (2008) The emerging functions of histone demethylases.Curr Opin Genet Dev 18: 159-168.
56. Shi Y (2007) Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet 8: 829-833.
57. Yoshimi A, Kurokawa M (2011) Key roles of histone methyltransferase and demethylase in leukemogenesis. J Cell Biochem 112: 415-424
58. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, et al. (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119: 941-953.
59. Lee MG, Wynder C, Cooch N, Shiekhattar R (2005) An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437: 432-435.
60. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, et al. (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437: 436-439
61. Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, et al. (2007) Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128: 505-518.
62. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, et al. (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138: 660-672.
63. Amente S, Bertoni A, Morano A, Lania L, Avvedimento EV, et al. (2010) LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription. Oncogene 29: 3691-3702.
64. Yang P, Wang Y, Chen J, Li H, Kang L, et al. (2011) RCOR2 is a subunit of the LSD1 complex that regulates ESC property and substitutes for SOX2 in reprogramming somatic cells to pluripotency. Stem Cells 29: 791-801.
65. Scoumanne A, Chen XB (2007) The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and -independent manners. Journal of Biological Chemistry 282: 15471-15475.
66. Forneris F, Binda C, Battaglioli E , Mattevi A (2008) LSD1: oxidative chemistry for multifaceted functions in chromatin regulation. Trends Biochem Sci 33: 181-189.
67. Nottke A, Colaiacovo MP, Shi Y(2009) Developmental roles of the histone lysine demethylases. Development 136: 879-889.
68. Sun G, Alzayady K, Stewart R, Ye P, Yang S, et al (2010) Histone demethylase LSD1 regulates neural stem cell proliferation. Mol Cell Biol 30: 1997-2005.
69. Cho H S, Suzuki T, Dohmae N, Hayami S, Unoki M, et al. (2011) Demethylation of RB Regulator MYPT1 by Histone Demethylase LSD1 Promotes Cell Cycle Progression in Cancer Cells. Cancer Research 71: 655-660.
70. Lv TF, Yuan DM, Miao XH, Lv YL, Zhan P, et al. (2012) Over-Expression of LSD1 Promotes Proliferation, Migration and Invasion in Non-Small Cell Lung Cancer. Plos One.
71. Huang Z, Li S, Song W, Li X, Li Q, et al. (2013) Lysine-specific demethylase 1 (LSD1/KDM1A) contributes to colorectal tumorigenesis via activation of the Wnt/beta-catenin pathway by down-regulating Dickkopf-1 (DKK1). PLoS One 8: e70077.
72. Ketscher A, Jilg CA, Willmann D, Hummel B, Imhof A, et al. (2014) LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6. Oncogenesis.
73. Niebel D, Kirfel J, Janzen V, Holler T, Majores M, et al. (2014) Lysine-specific demethylase 1 (LSD1) in hematopoietic and lymphoid neoplasms. Blood 124: 151-152.
74. Shixian L, Yebo S, Houbao L, Junyi H, Weiqi L, et al. (2015)Lysine-specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer. Oncotarget.
75. Wang M, Liu XH, Jiang GJ, Chen H, Guo J, et al. (2015) Relationship between LSD1 expression and E-cadherin expression in prostate cancer. International Urology and Nephrology 47: 485-490.
76. He Y, Yu H, Cai C, Sun S, Chai R, et al. (2015) Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis. Mol Neurobiol 52: 196-205.
77. He Y, Yu H, Sun S, Wang Y, Liu I, et al. (2013) Trans-2-phenylcyclopropylamine regulates zebrafish lateral line neuromast development mediated by depression of LSD1 activity. Int J Dev Biol 57: 365-373.
78. He Y, Tang D, Cai C, Chai R, Li H (2015) LSD1 is Required for Hair Cell Regeneration in Zebrafish. Mol Neurobiol.
79. Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, et al. (1999) Math1: an essential gene for the generation of inner ear hair cells. Science 284: 1837-1841.
80. Chen P, Johnson JE, Zoghbi HY, Segil N (2002) The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 129: 2495-2505.
81. Stojanova Z P, Kwan T , Segil N (2015) Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea. Development 142: 3529-3536.
82. Woods C, Montcouquiol M , Kelley MW (2004) Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat Neurosci 7: 1310-1318.
83. Pan N, Jahan I, Kersigo J, Kopecky B, Santi P, et al. (2011) Conditional deletion of Atoh1 using Pax2-Cre results in viable mice without differentiated cochlear hair cells that have lost most of the organ of Corti. Hear Res 275: 66-80.
84. Cai T, Seymour ML, Zhang H, Pereira FA, Groves AK (2013) Conditional deletion of Atoh1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti. J Neurosci 33: 10110-10122.
85. Chonko K T, Jahan I, Stone J, Wright MC, Fujiyama T, et al. (2013)Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. Dev Biol 381: 401-410.
86. Gubbels SP, WoessnerDW, Mitchell JC, Ricci AJ, Brigande JV (2008) Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature 455: 537-541.
87. Liu Z, Dearman JA, Cox BC, Walters BJ, Zhang L, et al. (2012)Age-dependent in vivo conversion of mouse cochlear pillar and Deiters cells to immature hair cells by Atoh1 ectopic expression. J Neurosci 32: 6600-6610.
88. Liu Z, Fang J, Dearman J, Zhang L, Zuo J (2014) In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression. PLoS One 9: e89377.
89. Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, et al. (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11: 271-276.
90. Izumikawa M, Batts SA, Miyazawa T, Swiderski D, Raphael Y (2008) Response of the flat cochlear epithelium to forced expression of Atoh1. Hear Res 240: 52-56.
91. Atkinson P J, Wise AK, Flynn BO, Nayagam BA, Richardson RT (2014)Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs. PLoS One 9: e102077.
92. Jansson L, Kim GS, Cheng AG (2015) Making sense of Wnt signaling-linking hair cell regeneration to development. Front Cell Neurosci 9: 66.
93. Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13: 767-779.
94. Logan C Y, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781-810.
95. Corwin J T, Cotanche DA (1988) Regeneration of sensory hair cells after acoustic trauma. Science 240: 1772-1774.
96. Ryals B M, Rubel EW (1988) Hair cell regeneration after acoustic trauma in adult Coturnix quail. Science 240: 1774-1776.
97. Bermingham-McDonogh O, Reh TA (2011) Regulated reprogramming in the regeneration of sensory receptor cells. Neuron 71: 389-405.
98. Jacques BE, Puligilla C, Weichert RM, Ferrer-Vaquer A, Hadjantonakis AK, et al. (2012) A dual function for canonical Wnt/beta-catenin signaling in the developing mammalian cochlea. Development 139: 4395-4404.
99. Chai R, Xia A, Wang T, Jan TA, Hayashi T, et al. (2011) Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. J Assoc Res Otolaryngol 12: 455-469.
100. Jan T A, Chai R, Sayyid ZN, van Amerongen R, Xia A, et al. (2013) Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. Development 140: 1196-1206.
101. Chai R, Kuo B, Wang T, Liaw EJ, Xia A, et al. (2012) Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea.Proc Natl Acad Sci U S A 109: 8167-8172.
102. He Y, Wang Z, Sun S, Tang D, Li W, et al. (2015)HDAC3 Is Required for Posterior Lateral Line Development in Zebrafish. Mol Neurobiol.
103. Shi F, Kempfle JS, Edge AS (2012) Wnt-responsive lgr5-expressing stem cells are hair cell progenitors in the cochlea. J Neurosci 32: 9639-9648.
104. Wang T, Chai R, Kim G, Pham X , Cheng A (2015) Damage-Recruited Lgr5+ Cells Regenerate Hair Cells via Proliferation and Direct Transdifferentiationin Neonatal Mouse Utricle. Nature Communications.
105. Shi F, Cheng YF, Wang XL, Edge AS (2010) Beta-catenin up-regulates Atoh1 expression in neural progenitor cells by interaction with an Atoh1 3' enhancer. J Biol Chem 285: 392-400.
106. Shi F, Hu L, Jacques BE, Mulvaney JF, Dabdoub A, et al. (2014) Beta-Catenin is required for hair-cell differentiation in the cochlea. J Neurosci 34: 6470-6479.
107. Shi F, Hu L, Edge AS (2013) Generation of hair cells in neonatal mice by beta-catenin overexpression in Lgr5-positive cochlear progenitors.Proc Natl Acad Sci U S A 110: 13851-13856.
108. Jan TA, Chai R, Sayyid ZN, van Amerongen R, Xia A, et al. (2013) Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. Development 140: 1196-1206.
109. Zak M, Klis SF, Grolman W (2015) The Wnt and Notch signalling pathways in the developing cochlea: Formation of hair cells and induction of regenerative potential. Int J Dev Neurosci 47: 247-258.
110. Brooker R, Hozumi K, Lewis J (2006) Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133: 1277-1286.
111. Hartman BH, Reh TA , Bermingham-McDonogh O (2010) Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear.Proc Natl Acad Sci U S A 107: 15792-15797.
112. Pan W, Jin Y, Chen J, Rottier RJ, Steel KP et al. (2013) Ectopic expression of activated notch or SOX2 reveals similar and unique roles in the development of the sensory cell progenitors in the mammalian inner ear. J Neurosci 33: 16146-16157.
113. Zine A, Aubert A, Qiu J, Therianos S, Guillemot F, et al. (2001) Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. J Neurosci 21: 4712-4720.
114. Batts S A, Shoemaker CR, Raphael Y (2009) Notch signaling and Hes labeling in the normal and drug-damaged organ of Corti. Hear Res 249: 15-22.
115. Korrapati S, Roux I, Glowatzki E, Doetzlhofer A (2013) Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea. PLoS One 8: e73276.
116. Mizutari K, Fujioka M, Hosoya M, Bramhall N, Okano HJ, et al. (2013)Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 77: 58-69.
117. Wang G P, Chatterjee I, Batts SA, Wong HT, Gong TW, et al. (2010) Notch signaling and Atoh1 expression during hair cell regeneration in the mouse utricle. Hear Res 267: 61-70.
118. Lin V, Golub JS, Nguyen TB, Hume CR, Oesterle EC, et al. (2011) Inhibition of Notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles. J Neurosci 31: 15329-15339.
119. Doetzlhofer A, Basch ML, Ohyama T, Gessler M, Groves AK, et al. (2009) Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell 16: 58-69.
120. Li W, Wu J, Yang J, Sun S, Chai R, et al. (2015) Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc Natl Acad Sci U S A 112: 166-171.
121. Zhao Y, Wang Y, Wang Z, Liu H, Shen Y, et al. (2006)Sonic hedgehog promotes mouse inner ear progenitor cell proliferation and hair cell generation in vitro.Neuroreport 17: 121-124.
122. Liu Z, Owen T, Zhang L, Zuo J (2010) Dynamic expression pattern of Sonic hedgehog in developing cochlear spiral ganglion neurons. Dev Dyn 239: 1674-1683.
123. Lu N, Chen Y, Wang Z, Chen G, Lin Q, et al. (2013) Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein. Biochem Biophys Res Commun 430: 700-705.
124. Driver E C, Pryor SP, Hill P, Turner J, Ruther U, et al. (2008) Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans. J Neurosci 28: 7350-7358.
125. Tateya T, Imayoshi I, Tateya I, Hamaguchi K, Torii H, et al. (2013) Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea. Development 140: 3848-3857
126. Wright T J, Mansour SL (2003) Fgf3 and Fgf10 are required for mouse otic placode induction. Development 130: 3379-3390.
127. Schimmang T (2007) Expression and functions of FGF ligands during early otic development. Int J Dev Biol 51: 473-481.
128. Chen J, Streit A (2013) Induction of the inner ear: stepwise specification of otic fate from multipotent progenitors. Hear Res 297: 3-12.
129. Pickles J O (2001) The expression of fibroblast growth factors and their receptors in the embryonic and neonatal mouse inner ear. Hear Res 155: 54-62.
130. Pirvola U, Ylikoski J, Trokovic R, Hebert JM, McConnell SK, et al. (2002) FGFR1 is required for the development of the auditory sensory epithelium. Neuron 35: 671-680.
131. Ono K, Kita T, Sato S, Neill PO, Mak SS, et al. (2014) FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation. PLoS Genet 10: e1004118.
132. Hayashi T, Ray CA, Bermingham-McDonogh O (2008) Fgf20 is required for sensory epithelial specification in the developing cochlea. J Neurosci 28: 5991-5999.
133. Pirvola U, Cao Y, Oellig C, Suoqiang Z, Pettersson RF, et al. (1995) The site of action of neuronal acidic fibroblast growth factor is the organ of Corti of the rat cochlea. Proc Natl Acad Sci U S A 92: 9269-9273.
134. Bermingham-McDonogh O, Stone JS, Reh TA, Rubel EW (2001) FGFR3 expression during development and regeneration of the chick inner ear sensory epithelia. Dev Biol 238: 247-259.
135. Ku Y C, Renaud NA, Veile RA, Helms C, Voelker CC, et al. (2014) The transcriptome of utricle hair cell regeneration in the avian inner ear. J Neurosci 34: 3523-3535.
136. Jayasena C S, Ohyama T, Segil N, Groves AK (2008)Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. Development 135: 2251-2261.
137. Agathocleous M, Iordanova I, Willardsen MI, Xue XY, Vetter ML, et al. (2009) A directional Wnt/beta-catenin-Sox2-proneural pathway regulates the transition from proliferation to differentiation in the Xenopus retina. Development 136: 3289-3299.
138. Bramhall N F, Shi F, Arnold K, Hochedlinger K, Edge AS (2014). Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Reports 2: 311-322.
139. Jacques BE, Puligilla C, Weichert RM, Ferrer-Vaquer A, Hadjantonakis AK, et al. (2012) A dual function for canonical Wnt/beta-catenin signaling in the developing mammalian cochlea. Development 139: 4395-4404.
140. Romero-Carvajal A, Navajas Acedo J, Jiang L, Kozlovskaja-Gumbriene A, R Alexander R, et al. (2015) Regeneration of Sensory Hair Cells Requires Localized Interactions between the Notch and Wnt Pathways. Dev Cell 34: 267-282.
141. Kuo B R, Baldwin EM, Layman WS, Taketo MM, Zuo J (2015) In Vivo Cochlear Hair Cell Generation and Survival by Coactivation of beta-Catenin and Atoh1. J Neurosci 35: 10786-10798.