EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear

Kozlowski, Mikolaj M.; Rudolf, Mark A.; Corwin, Jeffrey T.

doi:10.1523/jneurosci.2630-19.2020

Cited by 14 publications

(11 citation statements)

References 67 publications

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“…Hair cell injury to the chick utricle resulted in nuclear translocation of YAP1, but we did not observe this response in the mouse utricle, even after severe epithelial injury. These results, which are consistent with findings recently reported by other investigators [34][35][36][37] , suggest that the lack of YAP1 signaling following hair cell damage may be one factor that limits the regenerative ability of the mammalian ear.…”

Section: Discussionsupporting

confidence: 93%

Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

Borse

Barton

Arndt

et al. 2021

Sci Rep

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The Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear.

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Section: Discussionsupporting

confidence: 93%

Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

Borse

Barton

Arndt

et al. 2021

Sci Rep

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“…E-cadherin is reported to activate LATS1/2 independently of MST1/2 in other epithelia (Kim et al, 2011) and is expressed at much higher levels in mammalian SCs than in those of birds, fish, and amphibians (Collado et al, 2011b;Burns et al, 2013). Pharmacologic treatments that deplete E-cadherin from striolar SC junctions also affect YAP expression and induce SC proliferation (Kozlowski et al, 2020). Here, overexpression of YAP-S127A in mammalian SCs induced upregulation of E-cadherin in what may reflect negative feedback (Fig.…”

Section: Discussionmentioning

confidence: 75%

“…YAP-TEAD transcriptional activity can also induce negative feedback (Dai et al, 2015;Moroishi et al, 2015;Park et al, 2016). E-cadherin is reported to be a negative regulator of YAP in other epithelia (Kim et al, 2011;Benham-Pyle et al, 2015), and is hypothesized to restrict the activity of YAP in SCs of the mammalian utricle (Kozlowski et al, 2020). To test whether expression of YAP-S127A affects E-cadherin expression, we administered doxycycline to Yap-S127A 1/À ;Sox10 rtTA/1 mice and littermate controls at P1.…”

Section: Resultsmentioning

confidence: 99%

YAP Mediates Hair Cell Regeneration in Balance Organs of Chickens, But LATS Kinases Suppress Its Activity in Mice

et al. 2020

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Loss of sensory hair cells causes permanent hearing and balance deficits in humans and other mammals, but for nonmammals such deficits are temporary. Nonmammals recover hearing and balance sensitivity after supporting cells proliferate and differentiate into replacement hair cells. Evidence of mechanical differences between those sensory epithelia and their supporting cells prompted us to investigate whether the capacity to activate YAP, an effector in the mechanosensitive Hippo pathway, correlates with regenerative capacity in acceleration-sensing utricles of chickens and mice of both sexes. After hair cell ablation, YAP accumulated in supporting cell nuclei in chicken utricles and promoted regenerative proliferation, but YAP remained cytoplasmic and little proliferation occurred in mouse utricles. YAP localization in supporting cells was also more sensitive to shape change and inhibition of MST1/2 in chicken utricles than in mouse utricles. Genetic manipulations showed that in vivo expression of the YAP-S127A variant caused robust proliferation of neonatal mouse supporting cells, which produced progeny that expressed hair cell markers, but proliferative responses declined postnatally. Expression of YAP-5SA, which more effectively evades inhibitory phosphorylation, resulted in TEAD-dependent proliferation of striolar supporting cells, even in adult utricles. Conditional deletion of LATS1/2 kinases abolished the inhibitory phosphorylation of endogenous YAP and led to striolar proliferation in adult mouse utricles. The findings suggest that damage overcomes inhibitory Hippo signaling and facilitates regenerative proliferation in nonmammalian utricles, whereas constitutive LATS1/2 kinase activity suppresses YAP-TEAD signaling in mammalian utricles and contributes to maintaining the proliferative quiescence that appears to underlie the permanence of sensory deficits.

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“…In another study, we recently reported that treatments with EGF and a GSK3β inhibitor cause significant thinning of the circumferential F-actin bands in SCs throughout the sensory epithelium in utricles cultured from adult mice ( Kozlowski et al, 2020 ). With time, treatment with EGF and a GSK3β inhibitor caused depletion of E-cadherin at the junctions between SCs located within the striola and resulted in significant SC proliferation that was restricted to the striola.…”

Section: Discussionmentioning

confidence: 96%

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear

Rudolf

Andreeva²,

Kim³

et al. 2022

Front. Cell. Neurosci.

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The loss of inner ear hair cells causes permanent hearing and balance deficits in humans and other mammals, but non-mammals recover after supporting cells (SCs) divide and replace hair cells. The proliferative capacity of mammalian SCs declines as exceptionally thick circumferential F-actin bands develop at their adherens junctions. We hypothesized that the reinforced junctions were limiting regenerative responses of mammalian SCs by impeding changes in cell shape and epithelial tension. Using micropipette aspiration and atomic force microscopy, we measured mechanical properties of utricles from mice and chickens. Our data show that the epithelial surface of the mouse utricle stiffens significantly during postnatal maturation. This stiffening correlates with and is dependent on the postnatal accumulation of F-actin and the cross-linker Alpha-Actinin-4 at SC-SC junctions. In chicken utricles, where SCs lack junctional reinforcement, the epithelial surface remains compliant. There, SCs undergo oriented cell divisions and their apical surfaces progressively elongate throughout development, consistent with anisotropic intraepithelial tension. In chicken utricles, inhibition of actomyosin contractility led to drastic SC shape change and epithelial buckling, but neither occurred in mouse utricles. These findings suggest that species differences in the capacity for hair cell regeneration may be attributable in part to the differences in the stiffness and contractility of the actin cytoskeletal elements that reinforce adherens junctions and participate in regulation of the cell cycle.

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EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear

Cited by 14 publications

References 67 publications

Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

YAP Mediates Hair Cell Regeneration in Balance Organs of Chickens, But LATS Kinases Suppress Its Activity in Mice

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear

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