Gfi1‐Cre knock‐in mouse line: A tool for inner ear hair cell‐specific gene deletion

Yang, Hua; Gan, Jean; Xie, Xiaoling; Deng, Min; Li, Feng; Chen, Xiaowei; Gao, Zhiqiang; Gan, Lin

doi:10.1002/dvg.20632

Cited by 68 publications

(90 citation statements)

References 16 publications

(34 reference statements)

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“…To test if hair cells were responsive to Wnt/β-catenin signaling, we expressed β-catenin in hair cells. Gfi1 is expressed in the cochlea starting from E15.5 specifically in hair cells (18). Tomato reporter was seen in all hair cells in mutants of Gfi1-Cre crossed with Cre-activated tdTomato reporter mice (Fig.…”

Section: Inner Pillar Cells Showed Increased Lgr5 Expression and Divimentioning

confidence: 94%

Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors

Shi

Edge

2013

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

162

186

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Mammalian hair cells do not regenerate, and their loss is a major cause of deafness. We recently identified leucine-rich repeat containing, G-protein-coupled receptor 5 (Lgr5)-expressing cochlear supporting cells with the capacity for self-renewal and hair cell differentiation in vitro. We found that these cells, a subset of cochlear supporting cells, were responsive to Wnt signaling. Here we asked whether these Lgr5-positive cells, despite their lack of contribution to hair cell replacement after degenerative loss, could be driven by forced expression of β-catenin to act as hair cell progenitors in vivo. We showed that forced stabilization of β-catenin in supporting cells in neonatal animals resulted in proliferation of supporting cells and generation of hair cells. Although β-catenin expression was increased by genetic means in all supporting cells, entry to the cell cycle and differentiation to hair cells of the normally postmitotic cells was restricted to the Lgr5-positive population. Our finding suggests that Wnt/β-catenin can drive Lgr5-positive cells to act as hair cell progenitors, even after their exit from the cell cycle and apparent establishment of cell fate.

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Section: Inner Pillar Cells Showed Increased Lgr5 Expression and Divimentioning

confidence: 94%

Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors

Shi

Edge

2013

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

162

186

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“…Induced-DTR (iDTR) mice, which contain a loxP-flanked stop sequence upstream of the DT receptor (DTR) at the Rosa26 locus, were obtained from The Jackson Laboratory (Stock 007900; Buch et al, 2005). ␤-catenin flox(exon3) mice (Harada et al, 1999) were generously provided by M. Taketo (Kyoto University, Kyoto, Japan), Sox2-Cre-ER mice (Arnold et al, 2011) by K. Hochedlinger (Harvard Medical School, Boston, MA), and Gfi1-Cre mice (Yang et al, 2010) by L. Gan (University of Rochester, Rochester, NY). Rosa26 reporter mice, containing a loxPflanked stop cassette upstream of a red fluorescent protein variant (Stock 007914;Madisen et al, 2010), were obtained from The Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 99%

“…Gfi1 is expressed in auditory HCs from E15.5 through adulthood (Yang et al, 2010). DT was given at P1, and the cochlea was harvested at P4 from iDTR;Gfi1-Cre mice, in which Cre is driven by Gfi1.…”

Section: Death Of Hcs Induced By Dtmentioning

confidence: 99%

Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice

Chiang

et al. 2016

J. Neurosci.

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Cochlear hair cells (HCs), the sensory cells that respond to sound, do not regenerate after damage in adult mammals, and their loss is a major cause of deafness. Here we show that HC regeneration in newborn mouse ears occurred spontaneously when the original cells were ablated by treatment with diphtheria toxin (DT) in ears that had been engineered to overexpress the DT receptor, but was not detectable when HCs were ablated in vivo by the aminoglycoside antibiotic neomycin. A variety of Wnts (Wnt1, Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt7b, Wnt9a, Wnt9b, and Wnt11) and Wnt pathway component Krm2 were upregulated after DT damage. Nuclear ␤-catenin was upregulated in HCs and supporting cells of the DT-damaged cochlea. Pharmacological inhibition of Wnt decreased spontaneous regeneration, confirming a role of Wnt signaling in HC regeneration. Inhibition of Notch signaling further potentiated supporting cell proliferation and HC differentiation that occurred spontaneously. The absence of new HCs in the neomycin ears was correlated to less robust Wnt pathway activation, but the ears subjected to neomycin treatment nonetheless showed increased cell division and HC differentiation after subsequent forced upregulation of ␤-catenin. These studies suggest, first, that Wnt signaling plays a key role in regeneration, and, second, that the outcome of a regenerative response to damage in the newborn cochlea is determined by reaching a threshold level of Wnt signaling rather than its complete absence or presence.

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“…Furthermore, this antibody (clone 14a6) has been used to show the specific interaction (by reciprocal coimmunoprecipitation) of Brn3a and HMGA1 in ND7 cells (originating from fusion of rat neonatal primary sensory dorsal root ganglia neurons and mouse neuroblastoma cells; Esposito et al, 2010). This antibody (a-Brn3a, also known as a-Pou4f1) has been used to specifically identify RGCs in developing and adult mouse retina (Elshatory et al, 2007;Yang et al, 2010). RGC-specificity of this antibody is validated by colabeling of the same retinal (RGC) layer with two other RGC-specific antibodies, a-Pou4f2 (Yang et al, 2010) and a-NF-L (Moshiri et al, 2008).…”

Section: Antibody Characterizationmentioning

confidence: 99%

Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

Nasonkin

Lazo

Hambright

et al. 2011

J of Comparative Neurology

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DNA methyltransferases--DNMT1, DNMT3a, and DNMT3b--produce methylation patterns that dynamically regulate chromatin remodeling and gene expression. The vertebrate retina provides an ideal model to elucidate molecular control of neurogenesis as all neuronal cell types and Müller glia are generated in a conserved order from common pools of progenitor cells. As a prelude to exploring epigenetic regulation of mammalian retinal development, we investigated the expression of Dnmt1, Dnmt3a, and Dnmt3b in the mouse retina from embryonic day (E) 10.5 to 10 months of age. High levels of transcripts for all three Dnmt genes were observed in early stages of retinal differentiation, with significantly reduced expression after birth. Although DNMT1 protein is abundant in retinal progenitors at E10.5, it becomes restricted to postmitotic cells by E15.5. Most cells in the postnatal retina show nuclear immunostaining of DNMT1; however, the photoreceptors exhibit distinctive patterns. In rods, weak expression of DNMT1 is detected in perinuclear region and in the nucleus, whereas a strong nuclear labeling is evident in cones. DNMT3a and DNMT3b show a discrete pattern in developing retina with high expression at E11.5, little or no immunostaining by E15.5, and then postnatal expression overlapping with DNMT1 in early born neurons (ganglion, amacrine and horizontal cells, and cones). Robust nuclear localization of DNMTs in cones compared to rods suggests a potential role of DNA methylation in differential remodeling of chromatin in these two specialized neurons. Our studies indicate that DNA methyltransferases contribute to the establishment and maturation of cell fates during retinal development.

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Gfi1‐Cre knock‐in mouse line: A tool for inner ear hair cell‐specific gene deletion

Cited by 68 publications

References 16 publications

Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors

Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors

Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice

Distinct nuclear localization patterns of DNA methyltransferases in developing and mature mammalian retina

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