Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea

Chai, Renjie; Kuo, Bryan; Wang, Tian; Liaw, Eric J.; Xia, Anping; Jan, Taha A.; Li, Yong; Taketo, Makoto Mark; Oghalai, John S.; Nusse, Roeland; Zuo, Jian; Cheng, Alan G.

doi:10.1073/pnas.1202774109

Cited by 254 publications

(376 citation statements)

References 32 publications

(40 reference statements)

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“…Our work shows that in the neonatal mouse, HC progenitors and neural progenitors are different populations with different potencies. The cochlea-derived Lgr5-expressing cells produced HC-like cells, consistent with previous work (Chai et al, 2012;Shi et al, 2013Shi et al, , 2012), but did not produce neural cell types. We demonstrated that PLP1-expressing glial cells from the neonatal spiral ganglion were capable of differentiating both to neurons and to multiple forms of glia that are outside the otic lineage.…”

Section: Discussionsupporting

confidence: 77%

“…5D). tdTomato was not colocalized with Tuj1 in any cells (n=696 Tuj1 + cells), consistent with in situ data that localize Lgr5 to non-neuronal cells in the OC (Chai et al, 2012;Shi et al, 2012). Because we had previously shown (Martinez-Monedero et al, 2008;Oshima et al, 2007) that neurons could differentiate from inner ear spheres, we set out to identify an inner ear progenitor that gives rise to neurons.…”

Section: Progenitor Sub-populationssupporting

confidence: 71%

“…Lgr5 is expressed in inner border cells, inner pillar cells, and third row Deiters' cells (Chai et al, 2012;Shi et al, 2012) (Fig. 5A).…”

Section: Progenitor Sub-populationsmentioning

confidence: 99%

“…A subset of supporting cells in the early postnatal mouse OC expresses Lgr5 (Chai et al, 2012;Shi et al, 2012), a marker of stem cells of the intestinal epithelium (Barker et al, 2007). Lgr5 increases a cell's responsiveness to Wnt by potentiating the signal transmitted through frizzled (de Lau et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

McLean

Eatock

et al. 2016

Development

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Disorders of hearing and balance are most commonly associated with damage to cochlear and vestibular hair cells or neurons. Although these cells are not capable of spontaneous regeneration, progenitor cells in the hearing and balance organs of the neonatal mammalian inner ear have the capacity to generate new hair cells after damage. To investigate whether these cells are restricted in their differentiation capacity, we assessed the phenotypes of differentiated progenitor cells isolated from three compartments of the mouse inner ear -the vestibular and cochlear sensory epithelia and the spiral ganglion -by measuring electrophysiological properties and gene expression. Lgr5 + progenitor cells from the sensory epithelia gave rise to hair cell-like cells, but not neurons or glial cells. Newly created hair cell-like cells had hair bundle proteins, synaptic proteins and membrane proteins characteristic of the compartment of origin. PLP1 + glial cells from the spiral ganglion were identified as neural progenitors, which gave rise to neurons, astrocytes and oligodendrocytes, but not hair cells. Thus, distinct progenitor populations from the neonatal inner ear differentiate to cell types associated with their organ of origin.

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Section: Discussionsupporting

confidence: 77%

Section: Progenitor Sub-populationssupporting

confidence: 71%

“…Lgr5 is expressed in inner border cells, inner pillar cells, and third row Deiters' cells (Chai et al, 2012;Shi et al, 2012) (Fig. 5A).…”

Section: Progenitor Sub-populationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

McLean

Eatock

et al. 2016

Development

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“…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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The role of Wnt/β‐catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line

Jacques

Montgomery

Uribe

et al. 2013

Developmental Neurobiology

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Canonical Wnt/β-catenin signaling has been implicated in multiple developmental events including the regulation of proliferation, cell fate, and differentiation. In the inner ear, Wnt/β-catenin signaling is required from the earliest stages of otic placode specification through the formation of the mature cochlea. Within the avian inner ear, the basilar papilla (BP), many Wnt pathway components are expressed throughout development. Here, using reporter constructs for Wnt/β-catenin signaling, we show that this pathway is active throughout the BP (E6-E14) in both hair cells (HCs) and supporting cells. To characterize the role of Wnt/β-catenin activity in developing HCs, we performed gain- and loss-of-function experiments in vitro and in vivo in the chick BP and zebrafish lateral line systems, respectively. Pharmacological inhibition of Wnt signaling in the BP and lateral line neuromasts during the periods of proliferation and HC differentiation resulted in reduced proliferation and decreased HC formation. Conversely, pharmacological activation of this pathway significantly increased the number of HCs in the lateral line and BP. Results demonstrated that this increase was the result of up-regulated cell proliferation within the Sox2-positive cells of the prosensory domains. Furthermore, Wnt/β-catenin activation resulted in enhanced HC regeneration in the zebrafish lateral line following aminoglycoside-induced HC loss. Combined, our data suggest that Wnt/β-catenin signaling specifies the number of cells within the prosensory domain and subsequently the number of HCs. This ability to induce proliferation suggests that the modulation of Wnt/β-catenin signaling could play an important role in therapeutic HC regeneration.

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Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea

Cited by 254 publications

References 32 publications

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

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

The role of Wnt/β‐catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line

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