Dynamic Expression of Lgr5, a Wnt Target Gene, in the Developing and Mature Mouse Cochlea

Chai, Renjie; Xia, Anping; Jan, Taha A.; Hayashi, Toshinori; Bermingham‐McDonogh, Olivia; Cheng, Alan G.

doi:10.1007/s10162-011-0267-2

Cited by 144 publications

(159 citation statements)

References 60 publications

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“…S4), comparable to the levels observed in the E14.5 base. This pattern of activity was similar to that in reporter mice for Lgr5, a target of Wnt/-catenin signaling (Chai et al, 2011).…”

Section: Canonical Wnt Signaling Is Active In the Developing Mammaliasupporting

confidence: 72%

“…S1) and this pattern is maintained during postnatal stages (Simonneau et al, 2003). Recent analysis of reporter mice for downstream targets of Wnt/-catenin signaling (Chai et al, 2011) has suggested that this pathway might be active in the developing cochlea. In this study, we identify and characterize a dual role for Wnt/-catenin signaling during proliferation of the cochlear prosensory domain and during mechanosensory HC differentiation.…”

Section: Introductionmentioning

confidence: 94%

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A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

et al. 2012

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The canonical Wnt/β-catenin signaling pathway is known to play crucial roles in organogenesis by regulating both proliferation and differentiation. In the inner ear, this pathway has been shown to regulate the size of the otic placode from which the cochlea will arise; however, direct activity of canonical Wnt signaling as well as its function during cochlear mechanosensory hair cell development had yet to be identified. Using TCF/Lef:H2B-GFP reporter mice and transfection of an independent TCF/Lef reporter construct, we describe the pattern of canonical Wnt activity in the developing mouse cochlea. We show that prior to terminal mitosis, canonical Wnt activity is high in early prosensory cells from which hair cells and support cells will differentiate, and activity becomes reduced as development progresses. Using an in vitro model we demonstrate that Wnt/β-catenin signaling regulates both proliferation and hair cell differentiation within the developing cochlear duct. Inhibition of Wnt/β-catenin signaling blocks proliferation during early mitotic phases of development and inhibits hair cell formation in the differentiating organ of Corti. Conversely, activation increases the number of hair cells that differentiate and induces proliferation in prosensory cells, causing an expansion of the Sox2-positive prosensory domain. We further demonstrate that the induced proliferation of Sox2-positive cells may be mediated by the cell cycle regulator cyclin D1. Lastly, we provide evidence that the mitotic Sox2-positive cells are competent to differentiate into hair cells. Combined, our data suggest that Wnt/β-catenin signaling has a dual function in cochlear development, regulating both proliferation and hair cell differentiation.

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“…S4), comparable to the levels observed in the E14.5 base. This pattern of activity was similar to that in reporter mice for Lgr5, a target of Wnt/-catenin signaling (Chai et al, 2011).…”

Section: Canonical Wnt Signaling Is Active In the Developing Mammaliasupporting

confidence: 72%

Section: Introductionmentioning

confidence: 94%

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

et al. 2012

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“…P2 cochleae were then cultured and treated with DAPT (P2-P5) in the presence of EdU. In the DMSO-treated control, tdTomato expression was observed at day 5 in the SC subtypes, as previously reported (37). Neither EdU…”

Section: /Myo7asupporting

confidence: 57%

Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

Wu²,

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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154

157

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The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G proteincoupled receptor 5 (Lgr5

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“…GER cells are immediate neighbors of IBCs, IPhCs, and IHCs and may be less differentiated than SCs in the organ of Corti. GER cells exhibit higher levels of Wnt signaling (e.g., β-catenin and Lgr5) (38)(39)(40)52) and lower levels of Notch signaling (53) and respond readily to Atoh1 (atonal homolog 1) ectopic expression (54)(55)(56)(57). GER cells also express Nestin, a stem/progenitor cell marker in the central nervous system (58).…”

Section: Discussionmentioning

confidence: 99%

“…We used leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)CreER T2 ;Rosa26 DTA (Lgr5DTA) mice induced at P0 and P1 to ablate IBCs, IPhCs, a small population of GER cells (two or three rows of cells in the lateral GER close to the IHCs), and some inner PCs (IPCs) and DCs (Fig. S1C, targeted cells are shown in red) (34,(38)(39)(40)(41)(42). We also used GlastCreER T ;Rosa26 DTA (GlastDTA) mice to target IBCs, IPhCs, and a broader mosaic cell population of the entire GER after tamoxifen treatment at P0 and P1.…”

Section: Neonatal Ibc/iphc Ablation Does Not Impact Adult Spiral Gangmentioning

confidence: 99%

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Lagarde

Wan

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo. We demonstrate that the organ of Corti has the intrinsic capacity to replenish IBCs/IPhCs effectively during early postnatal development. Repopulation depends on the presence of hair cells and cells within the greater epithelial ridge and is independent of cell proliferation. This plastic response in the neonatal cochlea preserves neuronal survival, afferent innervation, and hearing sensitivity in adult mice. In contrast, the capacity for IBC/IPhC regeneration is lost in the mature organ of Corti, and consequently IHC survival and hearing sensitivity are impaired significantly, demonstrating that there is a critical period for the regeneration of cochlear supporting cells. Our findings indicate that the quiescent neonatal organ of Corti can replenish specific supporting cells completely after loss in vivo to guarantee mature hearing function.deafness | cell ablation | hair cell | organ of Corti | glia

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Dynamic Expression of Lgr5, a Wnt Target Gene, in the Developing and Mature Mouse Cochlea

Cited by 144 publications

References 60 publications

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

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