cProx1 immunoreactivity distinguishes progenitor cells and predicts hair cell fate during avian hair cell regeneration

Stone, Jennifer S.; Shang, Jia; Tomarev, Stanislav I.

doi:10.1002/dvdy.20087

Cited by 31 publications

(34 citation statements)

References 100 publications

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“…For example, Bhave et al (1995) found that 3% of quiescent SCs express detectable levels of proliferating cell nuclear antigen (PCNA). In addition, SCs across the neural-abneural axis of the BP express different levels of the transcription factor Prox1 (Stone et al, 2004) or transcripts for fibroblast growth factor receptor 3 (Bermingham-McDonogh et al, 2001). The functional significance of these different expression profiles has not been established.…”

Section: Properties Of Avian Supporting Cellsmentioning

confidence: 99%

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Hair cell regeneration in the avian auditory epithelium

Stone¹,

Cotanche²

2007

Int. J. Dev. Biol.

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210

191

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Regeneration of sensory hair cells in the mature avian inner ear was first described just over 20 years ago. Since then, it has been shown that many other non-mammalian species either continually produce new hair cells or regenerate them in response to trauma. However, mammals exhibit limited hair cell regeneration, particularly in the auditory epithelium. In birds and other non-mammals, regenerated hair cells arise from adjacent non-sensory (supporting) cells. Hair cell regeneration was initially described as a proliferative response whereby supporting cells re-enter the mitotic cycle, forming daughter cells that differentiate into either hair cells or supporting cells and thereby restore cytoarchitecture and function in the sensory epithelium. However, further analyses of the avian auditory epithelium (and amphibian vestibular epithelium) revealed a second regenerative mechanism, direct transdifferentiation, during which supporting cells change their gene expression and convert into hair cells without dividing. In the chicken auditory epithelium, these two distinct mechanisms show unique spatial and temporal patterns, suggesting they are differentially regulated. Current efforts are aimed at identifying signals that maintain supporting cells in a quiescent state or direct them to undergo direct transdifferentiation or cell division. Here, we review current knowledge about supporting cell properties and discuss candidate signaling molecules for regulating supporting cell behavior, in quiescence and after damage. While significant advances have been made in understanding regeneration in nonmammals over the last 20 years, we have yet to determine why the mammalian auditory epithelium lacks the ability to regenerate hair cells spontaneously and whether it is even capable of significant regeneration under additional circumstances. The continued study of mechanisms controlling regeneration in the avian auditory epithelium may lead to strategies for inducing significant and functional regeneration in mammals.

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Section: Properties Of Avian Supporting Cellsmentioning

confidence: 99%

“…However, differentiation of cells along the HC pathway has been studied to some extent (e.g., Stone and Rubel, 2000b;Roberson et al, 2004;Stone et al, 2004;Duncan et al, 2006;Cafaro et al, 2007). For example, some of the earliest known markers of HC differentiation are Myosins VI and VIIa.…”

Section: Differentiation In Post-mitotic Cellsmentioning

confidence: 99%

Hair cell regeneration in the avian auditory epithelium

Stone¹,

Cotanche²

2007

Int. J. Dev. Biol.

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210

191

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“…The upstream receptors and signaling proteins that regulate cAMP/PKA and B-Raf pathways could be restricted to a small subpopulation of "FSK-responsive" supporting cells. To date, only a few molecular markers, such as proliferation cell nuclear antigen (Bhave et al 1995), Prox1 transcription factor (Stone et al 2004) There is a delicate balance between stimulatory and inhibitory signals during the formation of replacement hair cells. Alternatively, all supporting cells could be induced to dividing by FSK-treatment.…”

Section: Future Directionsmentioning

confidence: 99%

“…The cochleas were immersed in 10% normal buffered formalin for at least 30 min followed by a 20-min incubation in 2N HCl, 0.1% Tween 20. BrdU was detected immunohistochemically as previously described (Stone et al 2004;Navaratnam et al 1996). BrdU-labeled nuclei were counted by two independent observers and the numbers combined in the analysis.…”

Section: Detection Of Brdumentioning

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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“…The chicken embryo has a well-defined pattern of markers in the otic placode, including expression of FGF-16 (Chapman et al, 2006), which overlaps with platelet-derived growth factor (PDGF) A and partly overlaps with BMP-4 expression. cProx1, an avian transcription factor, is regulated such that it may have a role in determining hair cell fate after progenitor cell proliferation (Stone et al, 2004). Expression of cNkx5-1, a chick homeobox gene, results in the induction and maintenance of rostral tissues and factors expressed by these tissues such as Pax-2 (Herbrand et al, 1998).…”

Section: Otic Restorationmentioning

confidence: 99%

Chicken embryo as a model for regenerative medicine

Coleman

2008

Birth Defects Research Pt C

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Although the chick embryo, including its extraembryonic membranes, has long been used as a model for developmental biology, its potential as a model for the repair and regeneration of adult human tissues is often overlooked. The chick offers a well-defined profile of intercellular and intracellular signaling pathways regulating the development of nearly every organ system in conjunction with great flexibility for chimeric and transgenic experiments. Depending upon the system of interest, the chick can either directly reflect the human condition, as in spinal cord repair or in chorioallantoic membrane wound healing, and therefore act as an in vivo model for repair, or mirror our aspired therapy as in limb generation or otic restoration and therefore act as our guide. With these unique opportunities, the chick embryo is certainly a model to be considered when aiming to develop a regenerative therapy for human applications.

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cProx1 immunoreactivity distinguishes progenitor cells and predicts hair cell fate during avian hair cell regeneration

Cited by 31 publications

References 100 publications

Hair cell regeneration in the avian auditory epithelium

Hair cell regeneration in the avian auditory epithelium

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

Chicken embryo as a model for regenerative medicine

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