Proliferation in the auditory receptor epithelium mediated by a cyclic AMP–dependent signaling pathway

Navaratnam, Dhasakumar; Su, Hongyan; Scott, Sean-Patrick; Oberholtzer, J. Carl

doi:10.1038/nm1096-1136

Cited by 53 publications

(42 citation statements)

References 24 publications

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“…Subsequently, postmitotic cells differentiate into either HCs or SCs. Previous studies demonstrated that SCs from the chicken BP reenter the cell cycle in organ cultures (Oesterle et al 1993;Navaratnam et al 1996;Warchol and Corwin 1996) and in pure SC cultures (Stone et al 1996) following HC loss. In this study, the distribution of dividing SCs was different in streptomycin-treated cultures than in control cultures.…”

Section: Patterns Of Sc Proliferation Vary In Control and Streptomycimentioning

confidence: 96%

“…Oesterle et al (1993) also showed that limited SC division occurs in organ cultures maintained without ototoxic drugs for 2 days. Other studies showed that substantial SC division occurs in organ cultures after drug damage (Navaratnam et al 1996;Daudet et al 2009) or HC ablation (Warchol andCorwin 1996), with some mitotic events leading to production of new HCs (Navaratnam et al 1996). In the current study, we examined the time course, levels, and spatial patterns of SC division and HC regeneration in cultured chicken BPs treated with streptomycin.…”

Section: Introductionmentioning

confidence: 99%

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Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Shang

Cafaro

Nehmer

et al. 2010

JARO

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In chickens, nonsensory supporting cells divide and regenerate auditory hair cells after injury. Anatomical evidence suggests that supporting cells can also transdifferentiate into hair cells without dividing. In this study, we characterized an organ culture model to study auditory hair cell regeneration, and we used these cultures to test if direct transdifferentiation alone can lead to significant hair cell regeneration. Control cultures (organs from posthatch chickens maintained without streptomycin) showed complete hair cell loss in the proximal (high-frequency) region by 5 days. In contrast, a 2-day treatment with streptomycin induced loss of hair cells from all regions by 3 days. Hair cell regeneration proceeded in culture, with the time course of supporting cell division and hair cell differentiation generally resembling in vivo patterns. The degree of supporting cell division depended upon the presence of streptomycin, the epithelial region, the type of culture media, and serum concentration. On average, 87% of the regenerated hair cells lacked the cell division marker BrdU despite its continuous presence, suggesting that most hair cells were regenerated via direct transdifferentiation. Addition of the DNA polymerase inhibitor aphidicolin to culture media prevented supporting cell division, but numerous hair cells were regenerated nonetheless. These hair cells showed signs of functional maturation, including stereociliary bundles and rapid uptake of FM1-43. These observations demonstrate that direct transdifferentiation is a significant mechanism of hair cell regeneration in the chicken auditory after streptomycin damage in vitro.

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Section: Patterns Of Sc Proliferation Vary In Control and Streptomycimentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Shang

Cafaro

Nehmer

et al. 2010

JARO

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“…FSK treatment induces supporting cell proliferation and ultimately the formation of replacement hair cells in the avian basilar papilla (Navaratnam et al 1996). Here, we determine the direct effects of FSK treatment in the basilar papilla by measuring the levels of cAMP after FSK treatments.…”

Section: Forskolin Treatment Induces Camp Accumulation In the Avian Bmentioning

confidence: 99%

“…In a previous study from our lab, we identified the cAMP/PKA pathway as the first signal transduction pathway in the formation of replacement hair cells in the avian auditory epithelium. We reported that treatment of undamaged cultured avian cochlear explants with several doses of the adenyl cyclase activator forskolin (FSK), or with cell-permeable cAMP analogs, induces DNA synthesis in auditory supporting cells and, after several days, results in the appearance of hair cells labeled with markers of DNA synthesis (Navaratnam et al 1996). Although supporting cell proliferation in the auditory epithelium can be mediated by FSK treatment, the cellular responses to FSK treatment in the basilar papilla and the downstream targets of the cAMP/PKA pathway have yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway

Bell

Oberholtzer

2010

JARO

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Sensorineural hearing deficiencies result from the loss of auditory hair cells. This hearing loss is permanent in humans and mammals because hair cells are not spontaneously replaced. In other animals such as birds, this is not the case. Damage to the avian cochlea evokes proliferation of supporting cells and the generation of functionally competent replacement hair cells. Signal transduction pathways are clinically useful as potential therapeutic targets, so there is significant interest in identifying the key signal transduction pathways that regulate the formation of replacement hair cells. In a previous study from our lab, we showed that forskolin (FSK) treatment induces auditory supporting cell proliferation and formation of replacement hair cells in the absence of sound or aminoglycoside treatment. Here, we show that FSK-induced supporting cell proliferation is mediated by cell-specific accumulation of cyclic adenosine monophosphate (cAMP) in avian supporting cells and the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. By a combination of immunostaining and pharmacological analyses, we show that FSK treatment increases cAMP levels in avian auditory supporting cells and that several ERK MAP inhibitors effectively block FSK-induced supporting cell proliferation. Next, we demonstrate by Western blotting and immunostaining analyses the expression of several ERK MAPK signaling molecules in the avian auditory epithelium and the cell-specific expression of B-Raf in avian auditory supporting cells. Collectively, these data suggest that FSK-induced supporting cell proliferation in the avian auditory epithelium is mediated by increases of cAMP levels in supporting cells and the cell-specific expression of the ERK MAPK family member B-Raf in supporting cells.

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“…Aminoglycoside antibiotics, such as neomycin, selectively kill hair cells in cultures of the avian ear organs (Navaratnam et al, 1996;Stone et al, 1996;Hirose et al, 1997;Kil et al, 1997;Warchol, 1999;Matsui et al, 2000a). To characterize the pattern of hair cell loss induced by neomycin, we incubated utricles in control (aminoglycoside-free) medium for 24 hr and then in 1 mM neomycin-supplemented medium for another 24 hr.…”

Section: Changes In Cell Survival and Nuclear Chromatin After Neomycimentioning

confidence: 99%

Inhibition of Caspases Prevents Ototoxic and Ongoing Hair Cell Death

2002

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Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment.Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dosedependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

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Proliferation in the auditory receptor epithelium mediated by a cyclic AMP–dependent signaling pathway

Cited by 53 publications

References 24 publications

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway

Inhibition of Caspases Prevents Ototoxic and Ongoing Hair Cell Death

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