The Genetics of Hair Cell Development and Regeneration

Groves, Andrew K.; Zhang, Kaidi D.; Fekete, Donna M.

doi:10.1146/annurev-neuro-062012-170309

Cited by 91 publications

(89 citation statements)

References 148 publications

(166 reference statements)

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“…It is well established that the inhibition of Notch signaling causes an increase in the number of hair cells in uninjured and injured chicken, guinea pig, and mouse utricles and cochleae and in injured zebrafish ears and lateral line neuromasts (52,53,(55)(56)(57)88). The presence of Notch is detrimental to hair cell differentiation, because it blocks the proneural gene atoh1a and thereby maintains support cells (9,13,65,89,90). The ability of support cells to transdifferentiate into hair cells after down-regulation of Notch signaling was exploited recently to restore a modest amount of hair cells in the injured adult mouse cochlea that led to some promising functional recovery of hearing (30).…”

Section: Notch Signaling Is Down-regulated Early In Lateral Line Hairmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

136

152

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Deafness caused by the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, nonmammalian animals (e.g., birds, amphibians, and fish) regenerate damaged hair cells. To understand better the reasons underpinning such disparities in regeneration among vertebrates, we set out to define at high resolution the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line. We performed RNA-Seq analyses on regenerating support cells purified by FACS. The resulting expression data were subjected to pathway enrichment analyses, and the differentially expressed genes were validated in vivo via whole-mount in situ hybridizations. We discovered that cell cycle regulators are expressed hours before the activation of Wnt/β-catenin signaling following hair cell death. We propose that Wnt/β-catenin signaling is not involved in regulating the onset of proliferation but governs proliferation at later stages of regeneration. In addition, and in marked contrast to mammals, our data clearly indicate that the Notch pathway is significantly down-regulated shortly after injury, thus uncovering a key difference between the zebrafish and mammalian responses to hair cell injury. Taken together, our findings lay the foundation for identifying differences in signaling pathway regulation that could be exploited as potential therapeutic targets to promote either sensory epithelium or hair cell regeneration in mammals.signaling pathway analysis | RNA sequencing | neuromast | Jak/Stat3 | cdkn1b

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Section: Notch Signaling Is Down-regulated Early In Lateral Line Hairmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

136

152

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“…In a similar process, early embryonic progenitors in the otic placode are specified to make the hearing and balance organs of the inner ear -the cochlea and vestibular organs -with specialized neurons, sensory HCs and supporting cells. This occurs through a wellchoreographed series of steps involving both innate genetic programs and inductive cues (Barald and Kelley, 2004;Groves et al, 2013;Raft and Groves, 2015). In previous studies, cells isolated from cochlear, vestibular, and neural inner ear compartments in the early postnatal mouse formed spheres that were thought to be multipotent, i.e.…”

Section: Introductionmentioning

confidence: 99%

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

McLean

Eatock

et al. 2016

Development

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Disorders of hearing and balance are most commonly associated with damage to cochlear and vestibular hair cells or neurons. Although these cells are not capable of spontaneous regeneration, progenitor cells in the hearing and balance organs of the neonatal mammalian inner ear have the capacity to generate new hair cells after damage. To investigate whether these cells are restricted in their differentiation capacity, we assessed the phenotypes of differentiated progenitor cells isolated from three compartments of the mouse inner ear -the vestibular and cochlear sensory epithelia and the spiral ganglion -by measuring electrophysiological properties and gene expression. Lgr5 + progenitor cells from the sensory epithelia gave rise to hair cell-like cells, but not neurons or glial cells. Newly created hair cell-like cells had hair bundle proteins, synaptic proteins and membrane proteins characteristic of the compartment of origin. PLP1 + glial cells from the spiral ganglion were identified as neural progenitors, which gave rise to neurons, astrocytes and oligodendrocytes, but not hair cells. Thus, distinct progenitor populations from the neonatal inner ear differentiate to cell types associated with their organ of origin.

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“…Therefore, damage to mammalian hair cells usually results in irreversible and permanent hearing loss. In recent years, regeneration of hair cells has yielded promising results (Groves et al, 2013;Hu and Ulfendahl 2013;Okano and Kelley 2012;Ronaghi et al, 2012;, and hair cell progenitors have been identified in the adult mammalian utricle and cochlea (Li et al, 2003;Mizutari et al, 2013;White et al, 2006). However, the existence of a specific progenitor population is still controversial (Hu and Ulfendahl 2013).…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Induces the Expression of Select Epithelial Genes in Mouse Utricle Sensory Epithelia-Derived Progenitor Cells

Wang

2014

Cellular Reprogramming

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Mouse utricle sensory epithelial cell-derived progenitor cells (MUCs), which have hair cell progenitor and mesenchymal features via epithelial-to-mesenchymal transition (EMT) as previously described, provide a potential approach for hair cell regeneration via cell transplantation. In this study, we treated MUCs with trichostatin A (TSA) to determine whether histone deacetylase inhibitor is able to stimulate the expression of epithelial genes in MUCs, an essential step for guiding mesenchymal-like MUCs to become sensory epithelial cells. After 72 h of TSA treatment, MUCs acquired epithelial-like features, which were indicated by increased expression of epithelial markers such as Cdh1, Krt18, and Dsp. Additionally, TSA decreased the expression of mesenchymal markers, including Zeb1, Zeb2, Snai1, and Snai2, and prosensory genes Lfng, Six1, and Dlx5. Moreover, the expression of the hair cell genes Atoh1 and Myo6 was increased in TSA-treated MUCs. We also observed significantly decreased expression of Hdac2 and Hdac3 in TSA-treated MUCs. However, no remarkable change was detected in protein expression using immunofluorescence, indicating that TSA-induced HDAC inhibition may contribute to the initial stage of the mesenchymal-to-epithelial phenotypic change. In the future, more work is needed to induce hair cell regeneration using inner ear tissue-derived progenitors to achieve an entire mesenchymal-to-epithelial transition.

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The Genetics of Hair Cell Development and Regeneration

Cited by 91 publications

References 148 publications

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

Histone Deacetylase Inhibitor Induces the Expression of Select Epithelial Genes in Mouse Utricle Sensory Epithelia-Derived Progenitor Cells

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