Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti

Hayashi, Toshinori; Cunningham, Dale E.; Bermingham‐McDonogh, Olivia

doi:10.1002/dvdy.21026

Cited by 108 publications

(116 citation statements)

References 24 publications

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“…Significantly, the hearing loss and supporting cell fate transformation are rescued when one copy of Fgf8 is removed from the Spry2-null background (Shim et al 2005). These data, together with the loss-of-function studies Hayashi et al 2007;Jacques et al 2007;Puligilla et al 2007;Zelarayan et al 2007), support the model of an FGF signaling gradient in the developing cochlear sensory epithelium in which support cell progenitors experiencing the highest levels of FGF8/ FGFR3 signaling differentiate as pillar cells, and those that are farther from the FGF source differentiate as Deiters' cells (Shim et al 2005).…”

mentioning

confidence: 56%

“…Thus, the cell fate transformation of two Deiters' cells to two pillar cells, identified as outer pillar-like cells based on CD44 staining, occurred gradually starting at E18.5 and finishing by P3. Attempts to determine whether the outer pillar-like cells seen in Fgfr3 P244R/+ cochleae retain any Deiters'-like character by labeling them with antibodies directed against S100A1 (Hayashi et al 2007;Puligilla et al 2007) were frustrated by persistent colabeling of pillar cells even in wild-type controls (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Normally, FGF8 promotes pillar cell differentiation by activating FGFR3 (Hayashi et al 2007;Jacques et al 2007;Puligilla et al 2007;Zelarayan et al 2007), so increasing FGF signaling by removing Spry2, the negative feedback regulator that is initially expressed broadly in cochlear support cells but eventually becomes restricted to Deiters' cells, causes one Deiters' cell to transform into a pillar cell by P7. This transformation is rescued by removing one copy of Fgf8 (Shim et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In the developing cochlear sensory epithelium, shared loss-of-function phenotypes suggest that FGF8, which is expressed specifically by the developing inner hair cell, signals through FGFR3, expressed in the laterally adjacent developing support cells, to promote differentiation of the two closest support cells as pillar cells. Thus, mice lacking Fgfr3 or humans carrying a presumed dominantnegative mutation in FGFR3 are hearing impaired, and the mice show incomplete differentiation of pillar cells Toydemir et al 2006;Hayashi et al 2007;Puligilla et al 2007). Similarly, mice lacking inner ear expression of Fgf8 also show aberrant pillar cell differentiation (Jacques et al 2007;Zelarayan et al 2007).…”

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confidence: 99%

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Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

Mansour

Urness

2013

Genes Dev.

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The stereotyped arrangement of cochlear sensory and supporting cells is critical for auditory function. Our previous studies showed that Muenke syndrome model mice (Fgfr3 P244R/+ ) have hearing loss associated with a supporting cell fate transformation of two Deiters' cells to two pillar cells. We investigated the developmental origins of this transformation and found that two prospective Deiters' cells switch to an outer pillar cell-like fate sequentially between embryonic day 17.5 (E17.5) and postnatal day 3 (P3). Unexpectedly, the Fgfr3 P244R/+ hearing loss and supporting cell fate transformation are not rescued by genetically reducing fibroblast growth factor 8 (FGF8), the FGF receptor 3c (FGFR3c) ligand required for pillar cell differentiation. Rather, reducing FGF10, which normally activates FGFR2b or FGFR1b, is sufficient for rescue of cochlear form and function. Accordingly, we found that the P244R mutation changes the specificity of FGFR3b and FGFR3c such that both acquire responsiveness to FGF10. Moreover, Fgf10 heterozygosity does not block the Fgfr3 P244R/+ supporting cell fate transformation but instead allows a gradual reversion of fate-switched cells toward the normal phenotype between P5 and at least P14. This study indicates that Deiters' and pillar cells can reversibly switch fates in an FGFdependent manner over a prolonged period of time. This property might be exploited for the regulation of sensory cell regeneration from support cells.

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mentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

Mansour

Urness

2013

Genes Dev.

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“…Notch1 mutations lead to increases in both OHC and IHC layers (Hayashi et al, 2008). Fgfr3 À/À mice show a deficiency in support cell differentiation and a slight increase in the number of OHC rows, with normal stereocilia bundle orientations (Hayashi et al, 2007). Exogenous Bmp4, a known target of Fgf3, produced an increase in the number of OHC rows from three to seven-nine rows when applied to cochlear explants by Bmp4-soaked beads (Puligilla et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

Dawe

Kooistra

Fairbridge

et al. 2011

Developmental Dynamics

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The loss of Cecr2, which encodes a chromatin remodeling protein, has been associated with the neural tube defect (NTD) exencephaly and open eyelids in mice. Here, we show that two independent mutations of Cecr2 are also associated with specific inner ear defects. Homozygous mutant 18.5 days post coitus (dpc) fetuses exhibited smaller cochleae as well as rotational defects of sensory cells and extra cell rows in the inner ear reminiscent of planar cell polarity (PCP) mutants. Cecr2 was expressed in the neuroepithelium, head mesenchyme, and the cochlear floor. Although limited genetic interaction for NTDs was seen with Vangl2, a microarray analysis of PCP genes did not reveal a direct connection to this pathway. The mechanism of Cecr2 action in neurogenesis and inner ear development is likely complex.

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CMV‐induced embryonic mouse organ of corti dysplasia: Network architecture of dysfunctional lateral inhibition

Melnick

Jaskoll

2015

Birth Defects Research

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Congenital CMV infection is the major non-genetic cause of sensorineural hearing loss at birth and beyond. Among other pathologies, there is a striking dysplasia/hyperplasia of organ of Corti hair and supporting cells (HC/SC). Using an in vitro embryonic mouse model of CMV-induced cochlear teratogenesis that mimics the known human pathology, and functional signaling network modeling, we tested the hypothesis that CMV disrupts the highly ordered HC/SC pattern by dysregulating Notch and Fgfr3, their cognate ligands and downstream effectors. Several novel emergent properties of the critical lateral inhibition subnetwork became apparent. The subnetwork has classic small-world properties such as short paths between most gene pairs, few long-distance links, and considerable clustering. Concomitantly, the calculated probability that our specific gene expression dataset is from dysplastic organs of Corti is highly significant (p < 1 × 10−12). Further, we determined that the subnetwork has a highly heterogeneous scale-free topology in which the highly linked genes (hubs), Notch and Fgfr3, play a central role in mediating interactions among the less linked genes. This phenomenon has important biologic and therapeutic implications.

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Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti

Cited by 108 publications

References 24 publications

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

CMV‐induced embryonic mouse organ of corti dysplasia: Network architecture of dysfunctional lateral inhibition

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