Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas

Yamamoto, Norio; Tanigaki, Kenji; Tsuji, Masazumi; Yabe, Daisuke; Ito, Juichi; Honjo, Tasuku

doi:10.1007/s00109-005-0706-9

Cited by 152 publications

(147 citation statements)

References 34 publications

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“…During embryonic development, activation of Notch signaling within a subset of prosensory cells inhibits the activation of a HC-specific program, limiting these cells to a SC fate (51)(52)(53). Inhibition of Notch signaling using γ-secretase inhibitors results in the generation of new HCs within the embryonic and neonatal murine cochlea (54)(55)(56); although the ability of SCs to dedifferentiate and convert to a HC fate declines rapidly within the first postnatal week of life. In the adult animal, only SCs located in the cochlear apex respond to Notch inhibition and infrequently convert to a HC fate (57).…”

Section: Lin28b Overexpression Results In a Delay In Prosensory Cell mentioning

confidence: 99%

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

Golden

Benito-Gonzalez

Doetzlhofer

2015

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

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Proper tissue development requires strict coordination of proliferation, growth, and differentiation. Strict coordination is particularly important for the auditory sensory epithelium, where deviations from the normal spatial and temporal pattern of auditory progenitor cell (prosensory cell) proliferation and differentiation result in abnormal cellular organization and, thus, auditory dysfunction. The molecular mechanisms involved in the timing and coordination of auditory prosensory proliferation and differentiation are poorly understood. Here we identify the RNAbinding protein LIN28B as a critical regulator of developmental timing in the murine cochlea. We show that Lin28b and its opposing let-7 miRNAs are differentially expressed in the auditory sensory lineage, with Lin28b being highly expressed in undifferentiated prosensory cells and let-7 miRNAs being highly expressed in their progeny-hair cells (HCs) and supporting cells (SCs). Using recently developed transgenic mouse models for LIN28B and let-7g, we demonstrate that prolonged LIN28B expression delays prosensory cell cycle withdrawal and differentiation, resulting in HC and SC patterning and maturation defects. Surprisingly, let-7g overexpression, although capable of inducing premature prosensory cell cycle exit, failed to induce premature HC differentiation, suggesting that LIN28B's functional role in the timing of differentiation uses let-7 independent mechanisms. Finally, we demonstrate that overexpression of LIN28B or let-7g can significantly alter the postnatal production of HCs in response to Notch inhibition; LIN28B has a positive effect on HC production, whereas let-7 antagonizes this process. Together, these results implicate a key role for the LIN28B/let-7 axis in regulating postnatal SC plasticity.Lin28b | Let-7 | hair cell | cochlea | regeneration

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Section: Lin28b Overexpression Results In a Delay In Prosensory Cell mentioning

confidence: 99%

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

Golden

Benito-Gonzalez

Doetzlhofer

2015

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

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“…Endogenous signaling within the progenitor cell population of each organ may give rise to cell types more representative of the differentiation capacity of each tissue. Production of HCs can be induced by Wnt activation (Shi et al, 2013 or Notch inhibition (Doetzlhofer et al, 2009;Mizutari et al, 2013;Pan et al, 2010;Yamamoto et al, 2006). Notchmediated lateral inhibition (Daudet and Lewis, 2005;Lanford et al, 1999) and innate Wnt signaling are both crucial for the development of HCs (Shi et al, 2013.…”

Section: Discussionmentioning

confidence: 99%

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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“…More significant hair cell overproduction phenotypes in cochlea that carried mutations in both Jag2 and Dll1 indicate that there is synergistic function between ligands, and loss of one Notch ligand in hair cells can be compensated by others (Kiernan et al, 2005). Therefore, Dll3 compensation could account for the mild phenotypes observed in Dll1 and Jag2 lossof-function studies as compared with Notch1 mutation or Notch inhibition experiments (Lanford et al, 1999;Yamamoto et al, 2006;Takebayashi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…First, conditional Notch1 mutations in the otic epithelium of FoxG1-Cre Notch flox/Ϫ mice resulted in a far more dramatic increase in hair cell numbers than that observed in the Dll1 hyp/Ϫ Jag2 Ϫ/Ϫ cochlea (Kiernan et al, 2005). Second, severe hair cell overproduction phenotypes were observed in cochlear explants treated with Notch1 antisense oligonucleotides or pharmacological inhibitors of Notch signaling (Zine et al, 2000;Yamamoto et al, 2006;Takebayashi et al, 2007). As noted above, there are additional Notch ligands, and their expression has not previously been described in the developing cochlea.…”

Section: Introductionmentioning

confidence: 99%

Dll3 is expressed in developing hair cells in the mammalian cochlea

Hartman

Hayashi

Nelson

et al. 2007

Developmental Dynamics

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Notch mediates the process of lateral inhibition that controls the production of hair cells in the inner ear. Hair cells are known to express Notch ligands Dll1 and Jag2, which signal through Notch1 in adjacent supporting cells. However, recent genetic and pharmacological studies indicate that the level of Notchmediated lateral inhibition is greater than can be accounted for by Dll1 and Jag2. Here, we report that another Notch ligand, Dll3, is expressed in developing hair cells, in a pattern that overlaps that of Dll1 and Jag2. We analyzed the cochleae of Dll3 pu mutant mice, but did not detect any abnormalities. However, earlier studies have demonstrated that there is functional redundancy among Notch ligands in cochlear development and loss of one ligand can be at least partially compensated for by another. Thus Dll3 may play a role in lateral inhibition similar to that of Dll1 and Jag2. Developmental Dynamics 236:2875-2883, 2007.

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Inhibition of Notch/RBP-J signaling induces hair cell formation in neonate mouse cochleas

Cited by 152 publications

References 34 publications

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

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

Dll3 is expressed in developing hair cells in the mammalian cochlea

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