Expression of the Pax2 transcription factor is associated with vestibular phenotype in the avian inner ear

Warchol, Mark E.; Richardson, Guy P.

doi:10.1002/dneu.20684

Cited by 12 publications

(13 citation statements)

References 38 publications

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“…16h–j) 30 . Together, these results indicate that stem-cell derived vesicles in our culture represent immature vestibular end organs, specifically the utricle and/or saccule 12,23,28 .…”

mentioning

confidence: 52%

“…We wished to reveal which type of hair cells populated the stem cell-derived sensory epithelia in our culture. Previous studies have suggested that expression of Pax2 and Sox2 may distinguish vestibular from cochlear hair cells 27,28 . Additionally, expression of the calcium binding protein Calretinin and Sox2 uniquely label Type II vestibular hair cells, whereas calyceal innervation from sensory neurons identifies Type I vestibular hair cells (Fig.…”

mentioning

confidence: 98%

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Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

Koehler

Mikosz

Molosh

et al. 2013

Nature

354

405

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The inner ear contains sensory epithelia that detect head movements, gravity and sound. It is unclear how to derive these sensory epithelia from pluripotent stem cells, a process which will be critical for modeling inner ear disorders or developing cell-based therapies for profound hearing loss and balance disorders1,2. To date, attempts to derive inner ear mechanosensitive hair cells and sensory neurons have resulted in inefficient or incomplete phenotypic conversion of stem cells into inner ear-like cells3–7. A key insight lacking from these previous studies is the importance of the non-neural and pre-placodal ectoderm, two critical precursors during inner ear development8–11. Here we report the step-wise differentiation of inner ear sensory epithelia from mouse embryonic stem cells (ESCs) in three-dimensional culture12,13. We show that by recapitulating in vivo development with precise temporal control of BMP, TGFβ and FGF signaling, ESC aggregates transform sequentially into non-neural, pre-placodal and otic placode-like epithelia. Remarkably, in a self-organized process that mimics normal development, vesicles containing prosensory cells emerge from the presumptive otic placodes and give rise to hair cells bearing stereocilia bundles and a kinocilium. Moreover, these stem cell-derived hair cells exhibit functional properties of native mechanosensitive hair cells and form specialized synapses with sensory neurons that have also arisen from ESCs in the culture. Finally, we demonstrate how these vesicles are structurally and biochemically comparable to developing vestibular end organs. Our data thus establish a novel in vitro model of inner ear differentiation that can be used to gain deeper insight into inner ear development and disorder.

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“…16h–j) 30 . Together, these results indicate that stem-cell derived vesicles in our culture represent immature vestibular end organs, specifically the utricle and/or saccule 12,23,28 .…”

mentioning

confidence: 52%

mentioning

confidence: 98%

Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

Koehler

Mikosz

Molosh

et al. 2013

Nature

354

405

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“…The second set of controls was comprised of utricles that were treated for 24 hours with 1 mM streptomycin and then allowed to recover in vitro for one or seven days. Previous studies have shown that culture in 1 mM streptomycin creates an extensive hair cell lesion and that significant hair cell regeneration is apparent after seven days recovery (Matsui et al, 2000; Warchol and Richardson, 2009). In the untreated utricles, we observed a ∼20% reduction in hair cell numbers over the eight day culture period (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cisplatin Ototoxicity Blocks Sensory Regeneration in the Avian Inner Ear

Slattery

Warchol²

2010

J. Neurosci.

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Cisplatin is a chemotherapeutic agent that is widely used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low-frequency (distal) region toward the high-frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin.

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“…Similarly the activity of Pax6 is involved in conferring progenitor status to neuronal populations in the spinal cord, cerebral cortex, adult hippocampus, and olfactory bulb (Grindley et al, 1995;Kohwi et al, 2005;Bel-Vialar et al, 2007;Tucker et al, 2008). Similarly, the expression of Pax2 and Pax8 is associated with proliferating progenitor populations in the developing kidney (Bouchard et al, 2002) and in the sensory patches of the inner ear (Li et al, 2004;Warchol and Richardson, 2009). Thus, the activity of Pax2 in the PPA is consistent with the generalized model of Pax function that has emerged (Blake et al, 2008).…”

Section: Control Of Cell Division By Pax2mentioning

confidence: 99%

Pax2 modulates proliferation during specification of the otic and epibranchial placodes

Freter¹,

Muta²,

O’Neill³

et al. 2012

Developmental Dynamics

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Background: The inner ear and epibranchial ganglia of vertebrates arise from a shared progenitor domain that is induced by FGF signalling, the posterior placodal area (PPA), before being segregated by Wnt signalling. One of the first genes activated in the PPA is the transcription factor Pax2. Loss-of-and gain-of function studies have defined a role for Pax2 in placodal morphogenesis and later inner ear development, but have not addressed the role Pax2 plays during the formation and maintenance of the PPA. Results: To understand the role of Pax2 during the development of the PPA, we used over-expression and repression of Pax2. Both gave rise to a smaller otocyst and repressed the formation of epibranchial placodes. In addition, cell cycle analysis revealed that Pax2 suppression reduced proliferation of the PPA. Key FindingsNeither suppression nor over-expression of Pax2 affects the extent of the precursor region of the inner ear and epibranchial placodes, the PPA. Suppressing and over-expressing Pax2 does affect the differentiation of the inner ear and the epibranchial placodes. Pax2 suppression reduces proliferation of PPA precursors.

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Expression of the Pax2 transcription factor is associated with vestibular phenotype in the avian inner ear

Cited by 12 publications

References 38 publications

Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture

Cisplatin Ototoxicity Blocks Sensory Regeneration in the Avian Inner Ear

Pax2 modulates proliferation during specification of the otic and epibranchial placodes

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