Notch Signaling Limits Supporting Cell Plasticity in the Hair Cell-Damaged Early Postnatal Murine Cochlea

Korrapati, Soumya; Roux, Isabelle; Glowatzki, Elisabeth; Doetzlhofer, Angelika

doi:10.1371/journal.pone.0073276

Cited by 78 publications

(79 citation statements)

References 78 publications

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“…The Notch pathway is of particular interest because experimental down-regulation of Notch induces transdifferentiation of mammalian support cells into hair cells (30,(52)(53)(54)(55)(56)(57). In contrast to previous reports in zebrafish and chicken (9, 13), our SPIA pathway analysis suggested that the Notch pathway is inhibited immediately after hair cell death because of simultaneous upregulation of numb (Fig.…”

Section: Resultscontrasting

confidence: 80%

“…In contrast to zebrafish, the Notch target genes are decreased only modestly, and Notch signaling is still active, in hair cell-depleted neonatal mouse cochleae and 3-to 4-wk-old mouse utricles (55,56,61). Therefore we hypothesize that the failure of transient Notch down-regulation in mammals could be one of the reasons that mammalian hair cells do not regenerate spontaneously after injury.…”

Section: Resultsmentioning

confidence: 92%

“…A growing number of studies have explored how the manipulation of Notch signaling could aid in regenerating mammalian hair cells. It is well established that the inhibition of Notch signaling causes an increase in the number of hair cells in uninjured and injured chicken, guinea pig, and mouse utricles and cochleae and in injured zebrafish ears and lateral line neuromasts (52,53,(55)(56)(57)88). The presence of Notch is detrimental to hair cell differentiation, because it blocks the proneural gene atoh1a and thereby maintains support cells (9,13,65,89,90).…”

Section: Notch Signaling Is Down-regulated Early In Lateral Line Hairmentioning

confidence: 99%

“…In the injured mammalian cochlea or utricle such drastic down-regulation of Notch target genes, such as Sox2 and several Hes and Hey genes, does not occur (55,56); the absence of such down-regulation could be one of the reasons mammalian hair cells do not regenerate.…”

Section: Notch Signaling Is Down-regulated Early In Lateral Line Hairmentioning

confidence: 99%

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Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

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

133

152

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Deafness caused by the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, nonmammalian animals (e.g., birds, amphibians, and fish) regenerate damaged hair cells. To understand better the reasons underpinning such disparities in regeneration among vertebrates, we set out to define at high resolution the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line. We performed RNA-Seq analyses on regenerating support cells purified by FACS. The resulting expression data were subjected to pathway enrichment analyses, and the differentially expressed genes were validated in vivo via whole-mount in situ hybridizations. We discovered that cell cycle regulators are expressed hours before the activation of Wnt/β-catenin signaling following hair cell death. We propose that Wnt/β-catenin signaling is not involved in regulating the onset of proliferation but governs proliferation at later stages of regeneration. In addition, and in marked contrast to mammals, our data clearly indicate that the Notch pathway is significantly down-regulated shortly after injury, thus uncovering a key difference between the zebrafish and mammalian responses to hair cell injury. Taken together, our findings lay the foundation for identifying differences in signaling pathway regulation that could be exploited as potential therapeutic targets to promote either sensory epithelium or hair cell regeneration in mammals.signaling pathway analysis | RNA sequencing | neuromast | Jak/Stat3 | cdkn1b

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Section: Resultscontrasting

confidence: 80%

Section: Resultsmentioning

confidence: 92%

Section: Notch Signaling Is Down-regulated Early In Lateral Line Hairmentioning

confidence: 99%

Section: Notch Signaling Is Down-regulated Early In Lateral Line Hairmentioning

confidence: 99%

See 2 more Smart Citations

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

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

133

152

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“…For nonmammalian vertebrates, SCs are the main source of postembryonic HC production and HC replenishment after trauma (76). Strikingly, mammalian SCs can generate HCs under certain permissive conditions, such as Notch inhibition or Wnt overstimulation, but this ability rapidly declines during the first week of life (57,(77)(78)(79). Here, we show that LIN28B reactivation in the early postnatal murine cochlea enhances the generation of new HCs in response to Notch inhibition.…”

Section: Lin28b Acts Through a Let-7-dependent Mechanism To Time Prosmentioning

confidence: 71%

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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Opposing expression gradients of calcitonin‐related polypeptide alpha (Calca/Cgrpα) and tyrosine hydroxylase (Th) in type II afferent neurons of the mouse cochlea

Vyas

Glowatzki

et al. 2017

J of Comparative Neurology

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Type II spiral ganglion neurons (SGNs) are small caliber, unmyelinated afferents that extend dendritic arbors hundreds of microns along the cochlear spiral, contacting many outer hair cells (OHCs). Despite these many contacts, type II afferents are insensitive to sound and only weakly depolarized by glutamate release from OHCs. Recent studies suggest that type II afferents may be cochlear nociceptors, and can be excited by ATP released during tissue damage, by analogy to somatic pain-sensing C-fibers. The present work compares the expression patterns among cochlear type II afferents of two genes found in C-fibers: calcitonin-related polypeptide alpha (Calca/Cgrpα), specific to pain-sensing C-fibers, and tyrosine hydroxylase (Th), specific to low-threshold mechanoreceptive C-fibers, which was shown previously to be a selective biomarker of type II versus type I cochlear afferents (Vyas et al., ). Whole-mount cochlear preparations from 3-week- to 2-month-old CGRPα-EGFP (GENSAT) mice showed expression of Cgrpα in a subset of SGNs with type II-like peripheral dendrites extending beneath OHCs. Double labeling with other molecular markers confirmed that the labeled SGNs were neither type I SGNs nor olivocochlear efferents. Cgrpα starts to express in type II SGNs before hearing onset, but the expression level declines in the adult. The expression patterns of Cgrpα and Th formed opposing gradients, with Th being preferentially expressed in apical and Cgrpα in basal type II afferent neurons, indicating heterogeneity among type II afferent neurons. The expression of Th and Cgrpα was not mutually exclusive and co-expression could be observed, most abundantly in the middle cochlear turn.

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Notch Signaling Limits Supporting Cell Plasticity in the Hair Cell-Damaged Early Postnatal Murine Cochlea

Cited by 78 publications

References 78 publications

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

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

Opposing expression gradients of calcitonin‐related polypeptide alpha (Calca/Cgrpα) and tyrosine hydroxylase (Th) in type II afferent neurons of the mouse cochlea

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