Elastic force restricts growth of the murine utricle

Gnedeva, Ksenia; Jacobo, Adrián; Salvi, Joshua D.; Petelski, Aleksandra A.; Hudspeth, A. J.

doi:10.7554/elife.25681

Cited by 33 publications

(43 citation statements)

References 61 publications

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“…Specimens were immunolabeled for myosin Vlla (hair cells), Sox2 (supporting cell and type II hair cells) and YAP1. Consistent with earlier studies 6 , we found that YAP1 expression was mainly confined to the cytoplasm of supporting cells and that its expression levels decreased with time. Interestingly, we also observed YAP1 expression in the cytoplasm of a subset of hair cells until P7, but YAP1 expression in hair cells was lost by P15 ( Fig.…”

Section: Developmental Profile Of Yap1 Expression In the Mouse Utriclsupporting

confidence: 92%

“…YAP1 signaling has been shown to play an important role in the development of the mouse utricle. Gnedeva et al, (2017) report that reduced mechanical stress in the sensory epithelium of the growing utricle promotes nuclear translocation of YAP1 and increased proliferation. It is not clear, however, whether YAP1 signaling is also required for regeneration after hair cell injury.…”

Section: Introductionmentioning

confidence: 99%

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

Borse

Barton

Arndt

et al. 2020

Preprint

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The Hippo pathway is an evolutionarily conserved signaling pathway involved in regulating organ size, development, homeostasis and regeneration [1][2][3][4] . YAP1 is a transcriptional coactivator and the primary effector of Hippo signaling. Upstream activation of the Hippo pathway leads to nuclear translocation of YAP1, which then evokes changes in gene expression and cell cycle entry 5 . A prior study has demonstrated nuclear translocation of YAP1 in the supporting cells of the developing utricle 6 , but the possible role of YAP1 in hair cell regeneration is unclear. The present study characterizes the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after hair cell injury. During neonatal development of the mouse utricle, YAP1 expression was observed in the cytoplasm ofsupporting cells, and was also transiently expressed in the cytoplasm of hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle at short time periods after placement in organotypic culture. However, little or no nuclear translocation of YAP1 was observed after injury to the utricles of neonatal or mature mice. In contrast, a significant degree of YAP1 nuclear translocation was observed in the chicken utricle after streptomycin-induced hair cell damage in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may be partly responsible for the distinct regenerative abilities of the avian vs. mammalian inner ear.

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Section: Developmental Profile Of Yap1 Expression In the Mouse Utriclsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Borse

Barton

Arndt

et al. 2020

Preprint

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“…4G,H). Consistent with our demonstration of a role for Yap in the development of the utricular sensory epithelium41 , most of these Yap-target genes were also highly expressed in E17.5 supporting cells.…”

supporting

confidence: 89%

“…The regenerative potential of the Hippo pathway has become abundantly clear in numerous organs, including the heart 5, [14][15][16] , retina 17 , liver, and intestine 18 . We earlier demonstrated that Hippo signaling limits the size of the developing murine utricle, a vestibular sensory organ, and that the Yap-Tead complex is active during-and necessary for-proliferative regeneration in the neonatal utricle 19 . These observations suggested that chemical activation of Yap signaling might engender supporting-cell proliferation in adult tissue, a key missing step in the regeneration of the mammalian inner ear.…”

Section: Introductionmentioning

confidence: 99%

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Kastan

Gnedeva

Alisch

et al. 2020

Preprint

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Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs 1-3 . Using a high-throughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yapdependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the substance fosters both the G1-S and G2-M checkpoint transitions and yields supporting cells capable of transdifferentiation. Upon withdrawal of the compound, a subset of supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. Viral transfection of Atoh1 induces the expression of hair cellspecific proteins in progeny. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. This project was made possible by the dedicated personnel of two service facilities. At Rockefeller University's High-Throughput Screening Resource Center directed by Fraser Glickman, Carolina Adura Alcaino helped design assays for enzyme activity. assisted with assay design and Rui Liang performed chemical syntheses. Declaration of InterestsKG, NK, TA, AAP, and AJH are parties to an application for patent protection of derivatives of the Lats inhibitor presented here.

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“…To address this question, we labeled hair cell progenitors using Plp‐CreER T2 :Rosa26 tdTomato mice starting at P2 and fate‐mapped them over time. The numbers of labeled hair cells nearly doubled between P9 and P30, likely due to differentiation of hair cell precursors, since previous studies showed that supporting cells are quiescent after P2 (Burns et al, ; Gnedeva, Jacobo, Salvi, Petelski, & Hudspeth, ). Using markers of hair cells and calyces, we determined that the vast majority of hair cells derived from Plp‐CreER T2 ‐expressing cells between P2 and P30 were Type II and were added primarily to the extrastriolar zones.…”

Section: Discussionmentioning

confidence: 86%

Development of hair cell phenotype and calyx nerve terminals in the neonatal mouse utricle

Warchol

Massoodnia

Pujol

et al. 2019

J of Comparative Neurology

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The vestibular organs of reptiles, birds, and mammals possess Type I and Type II sensory hair cells, which have distinct morphologies, physiology, and innervation. Little is known about how vestibular hair cells adopt a Type I or Type II identity or acquire proper innervation. One distinguishing marker is the transcription factor Sox2, which is expressed in all developing hair cells but persists only in Type II hair cells in maturity. We examined Sox2 expression and formation of afferent nerve terminals in mouse utricles between postnatal days 0 (P0) and P17. Between P3 and P14, many hair cells lost Sox2 immunoreactivity and the density of calyceal afferent nerve terminals (specific to Type I hair cells) increased in all regions of the utricle. At early time points, many calyces enclosed Sox2‐labeled hair cells, while some Sox2‐negative hair cells within the striola had not yet developed a calyx. These observations indicate that calyx maturation is not temporally correlated with loss of Sox2 expression in Type I hair cells. To determine which type(s) of hair cells are formed postnatally, we fate‐mapped neonatal supporting cells by injecting Plp‐CreER T2:Rosa26 tdTomato mice with tamoxifen at P2 and P3. At P9, tdTomato‐positive hair cells were immature and not classifiable by type. At P30, tdTomato‐positive hair cells increased 1.8‐fold compared to P9, and 91% of tdTomato‐labeled hair cells were Type II. Our findings show that most neonatally‐derived hair cells become Type II, and many Type I hair cells (formed before P2) downregulate Sox2 and acquire calyces between P0 and P14.

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Elastic force restricts growth of the murine utricle

Cited by 33 publications

References 61 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

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Development of hair cell phenotype and calyx nerve terminals in the neonatal mouse utricle

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